Arylamino fused pyrimidines

ABSTRACT

Corticotropin releasing factor (CRF) antagonists of formula I or formula II: and their use in treating anxiety, depression, and other psychiatric and neurological disorders.

This application claims the benefit of the filing of U.S. Provisional application Ser. No. 60/014,157, filed Mar. 27, 1996, U.S. Provisional application Ser. No. 60/030,536, filed Oct. 31, 1996 and U.S. Provisional application Ser. No. 60/039,124, filed Feb. 25, 1997.

FIELD OF THE INVENTION

This invention relates to novel compounds and pharmaceutical compositions, and to methods of using same in the treatment of psychiatric disorders and neurological diseases including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders.

BACKGROUND OF THE INVENTION

Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin(POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E. B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)]. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

There has also been a role postulated for CRF in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces "anxiolytic-like" effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)]. Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the "anxiogenic" effects of CRF in both the conflict test [K.T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Ro15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a- helical CRF₉₋₄₁) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces "anxiolytic-like" effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

DuPont Merck PCT application US94/11050 describes corticotropin releasing factor antagonist compounds of the formula: ##STR2## and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: ##STR3## where: V is CR^(1a) or N; Z is CR² or N; A is CR³⁰ or N; and D is CR²⁸ or N.

Pfizer WO 95/33750 describes corticotropin releasing factor antagonist compounds useful in the treatment of CNS and stress disorders. The description includes compounds of the formulae: ##STR4## where A is CR₇ or N; B is --NR₁ NR₂ ; R₁ is substituted or unsubstituted alkyl; R₂ is substituted or unsubstituted alkyl, aryl or heteroaryl; R₃ is methyl, halo, cyano, methoxy, etc.; R₄ is H, substituted or unsubstituted alkyl, halo, amino, nitro, etc.; R₅ is substituted or unsubstituted aryl or heteroaryl; R₆ is H or substituted or unsubstituted alkyl; R₇ is H, methyl, halo, cyano, etc.; R₁₆ and R₁₇ taken together form an oxo (=O) group; and G is =O, =S, =NH, =NcH₃, hydrogen, methyl, methoxy, etc. Pfizer WO 95/33750 also describes intermediates of the formula: ##STR5## where A can be N, D can be OH, R₄ can be nitro, R₁₉ is methyl or ethyl, Z can be NH or N(CH₃), and R₅ is substituted phenyl or substituted pyridyl, each substituted with 2 or 3 substituents selected from C1-C4 alkyl, chloro and bromo.

Pfizer WO 95/34563 describes corticotropin releasing factor antagonist compounds, including compounds of the formula: ##STR6## where A, B and the R groups have definitions similar to those in WO 95/33750.

Pfizer WO 95/33727 describes corticotropin releasing factor antagonist compounds of the formula: ##STR7## where A is CH₂ and Z can be a heteroaryl moiety.

Ganguly et al., U.S. Pat. No. 4,076,711 describes triazolo[4,5-d]pyrimidines of the formula: ##STR8## where X is halo, --NR₁ R or alkoxy, with R1 and R each being H or alkyl; Y is alkyl, cycloalkyl, hydroxycycloalkyl, phenyl, bicycloalkyl or phenylalkyl or bicycloalkylalkyl; and Q is H or Y. The patent states that the compounds are useful in the treatment of psoriasis.

Tanji et al., Chem. Pharm. Bull. 39(11)3037-3040(1991), describes triazolo[4,5-d]pyrimidines of the formula: ##STR9## where halo is I, Br or Cl, Ph is phenyl and Me is methyl. No utility for the compounds is described.

Settimo et al., Il Farmaco, Ed. Sc., 35 (4), 308-323 (1980) describes 8-azaadenines (triazolo[4,5-d] pyrimidines) of the formula: ##STR10## where R1 is H or benzyl and R2 is p-methylphenyl.

Biagi et al., I1 Farmaco, 49 (3), 183-186 (1994), describes N(6)-substituted 2-n-butyl-9-benzyl-8-azaadenines of the formula: ##STR11## where R² can be alkyl, phenyl, or benzyl. The paper states that the compounds have affinity for adenosine receptors.

Thompson et al., J. Med. Chem., 1991, 34, 2877-2882, describes N⁶,9-disubstituted adenines of the formula: ##STR12## where Ph is phenyl or (when C-2 is unsubstituted) 2-fluorophenyl. The paper states that the compounds have selective affinity for the Al adenosine receptor.

Kelley et al., J. Med. Chem. 1990, 31, 606-612, describes the compound ##STR13## where R⁶ is NHC₆ H₅ and R⁹ is CH₂ C₆ H₅, and reports that the compound was inactive when tested for anticonvulsant activity. The paper reports that various 6-(alkylamino)-9-benzyl-9H-purine analogs of the above compound exhibited anticonvulsant activity.

Kelley et al., J. Med. Chem. 1990, 33, 1360-1363, describes 6-anilino-9-benzyl-2-choro-9H-purines of the formula: ##STR14## where Bz is benzyl or (when R⁴ is H) p-methylbenzyl and R⁴ is H or alkyl, alkoxy, halo, cyano, nitro, etc. Tests of the compounds for antirhinoviral activity are reported.

Kelley et al., J. Heterocyclic Chem., 28, 1099 (1991), describes 6-substituted-9-(3-formamidobenzyl)-9H-purines of the formula: ##STR15## where R1 is NH2 or NHCHO. The compound where R1 is NHCHO was tested for benzodiazepine receptor binding and was inactive, although various analogs were active.

Khairy et al., J. Heterocyclic Chem., 22, 853 (1985), describes synthesis of certain 9-aryl-9H-purin-6-amines of the formula: ##STR16## where the R groups are H, methyl, ethyl, isopropyl, chloro or fluoro.

SUMMARY OF THE INVENTION

This invention is a class of novel compounds which are CRF receptor antagonists and which can be represented by formula I or formula II: ##STR17## or a pharmaceutically acceptable salt or pro-drug form thereof, wherein: X is N or CR¹ ;

Y is N or CR² ;

Z is NR³, O, or S(O)n;

G is O or S;

Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 5 R⁵ groups;

R¹ is independently at each occurrence H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, halo, CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, NR⁹ COR¹⁰, --OR¹¹, SH or --S(O)_(n) R¹² ;

R² is H, C₁ -C₄ alkyl, C₁ -C₆ cycloalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, C₁ -C₄ haloalkyl, --OR⁷, SH or --S(O)_(n) R¹² ;

R³ is H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C_(2-C) ₁₀ alkynyl, C₃ -C₈ cycloalkyl or C₄ -C₁₂ cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --CONR⁶ R⁷, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --CoR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ;

R⁴ is H, C₁ -C₄ alkyl, allyl, or propargyl, where C₁ -C₄ alkyl, allyl, or propargyl is optionally substituted with C₃ -C₆ cycloalkyl and where C₁ -C₄ alkyl is optionally substituted with, --OR⁷, --S(O)_(n) R¹² or --CO₂ R⁷ ;

R⁵ is independently at each occurrence C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, --CO(NOR⁹)R⁷, CO₂ R⁷, or --S(O)_(n) R⁷, where C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, CO₂ R⁷, --CO(NOR⁹)R⁷, or --S(O)_(n) R⁷ ;

R⁶ and R⁷ are independently at each occurrence H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; or NR⁶ R⁷ is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl;

R¹³ is C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl , pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --CoR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ;

n is independently at each occurrence 0, 1 or 2;

provided that R⁴ in formula I is not H:

(a) when X is N, Y is N, Z is NR³, R¹ is H, R³ is H or benzyl, and Ar is p-methylphenyl;

(b) when X is N, Y is N, Z is NR³, R¹ is butyl, R³ is benzyl, and Ar is phenyl;

(c) when X is N, Y is CH, Z is NR³, R³ is methyl, R¹ is H, and Ar is phenyl or 2-fluorophenyl;

(d) when X is N, Y is CH, Z is NR³, R³ is methyl, R¹ is Cl and Ar is phenyl;

(e) when X is N, Y is CH, Z is NR³, R¹ is Cl, R³ is benzyl, and Ar is phenyl or substituted phenyl;

(f) when X is N, Y is CH, Z is NR³, R³ is p-methylbenzyl, and Ar is phenyl;

(g) when X is N, Y is CR², Z is NR³, R² is CH₃, R³ is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro;

(h) when X is N, Y is N, Z is NR³, R³ is cyclopropylmethyl, R¹ is H, and Ar is 2-bromo-4-isopropylphenyl, or

(i) when X is N, Y is N, Z is S, R¹ is H, and Ar is 2-bromo-4-isopropylphenyl.

Preferred compounds of this invention are compounds of formula I and formula II and pharmaceutically acceptable salts and pro-drug forms thereof, wherein, independently or concurrently:

X is N or CR¹ ;

Y is N or CR² ;

Z is NR³, O, or S(O)_(n) ;

G is O or S;

Ar is phenyl or pyridyl, each optionally substituted with 1 to 3 R⁵ groups;

R¹ is independently at each occurrence H, C₁ -C₄ alkyl, halo, CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, --OR¹¹ or --S(O)_(n) R¹² ;

R² is H, C₁ -C₄ alkyl, C₁ -C₆ cycloalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, C₁ -C₄ haloalkyl, --OR⁷ or --S(O)_(n) R¹² ;

R³ is H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl or C₄ -C₁₂ cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, aryl and heteroaryl, where the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, and --NR⁶ R⁷ ;

R⁴ is H, C₁ -C₄ alkyl, allyl, or propargyl;

R⁵ is independently at each occurrence C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₈ cycloalkylalkyl, --NO₂, halo, --CN C₁ -C₄ haloalkyl, --NR⁶ R⁷, COR⁷ --OR⁷, --CONR⁶ R⁷, --CO(NOR⁹)R⁷, CO₂ R⁷, or --S(O)_(n) R⁷, where C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷, --CO(NOR⁹)R⁷, or --S(O)_(n) R⁷ ;

R⁶ and R⁷ are independently at each occurrence H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; or NR⁶ R⁷ is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine;

R⁸ is independently at each occurrence H or C₁ -C₄ alkyl;

R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl;

R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl;

R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl;

R¹³ C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-;

aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁸, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹², and --NR⁶ R⁷ ;

heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁸, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹², and --NR⁶ R⁷ ;

n is independently at each occurrence 0, 1 or 2.

Of the preferred compounds, more preferred are those of formula I wherein Z is NR³ and pharmaceutically acceptable salts and pro-drug forms thereof.

Included in this invention is the method of treating affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, or fertility problem in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of formula I or II.

Also included in this invention are pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of any one of the above-described compounds.

This invention also includes intermediate compounds useful in preparation of the CRF antagonist compounds and processes for making those intermediates, as described in the following description and claims.

The CRF antagonist compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION

Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention.

Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

The term "alkyl" includes both branched and straight-chain alkyl having the specified number of carbon atoms. "Alkenyl" includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. "Alkynyl" includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. "Haloalkyl" is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; "alkoxy" represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; "cycloalkyl" is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. "Halo" or "halogen" includes fluoro, chloro, bromo, and iodo.

The term "substituted", as used herein, means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., =O), then 2 hydrogens on the atom are replaced.

Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

The term "appropriate amino acid protecting group" means any group known in the art of organic synthesis for the protection of amine or carboxylic acid groups. Such amine protecting groups include those listed in Greene and Wuts, "Protective Groups in Organic Synthesis" John Wiley & Sons, New York (1991) and "The Peptides: Analysis, Synthesis, Biology, Vol. 3, Academic Press, New York (1981), the disclosure of which is hereby incorporated by reference. Any amine protecting group known in the art can be used. Examples of amine protecting groups include, but are not limited to, the following: 1) acyl types such as formyl, trifluoroacetyl, phthalyl, and p-toluenesulfonyl; 2) aromatic carbamate types such as benzyloxycarbonyl (Cbz) and substituted benzyloxycarbonyls, 1-(p-biphenyl)-1-methylethoxycarbonyl, and 9-fluorenylmethyloxycarbonyl (Fmoc); 3) aliphatic carbamate types such as tert-butyloxycarbonyl (Boc), ethoxycarbonyl, diisopropylmethoxycarbonyl, and allyloxycarbonyl; 4) cyclic alkyl carbamate types such as cyclopentyloxycarbonyl and adamantyloxycarbonyl; 5) alkyl types such as triphenylmethyl and benzyl; 6) trialkylsilane such as trimethylsilane; and 7) thiol containing types such as phenylthiocarbonyl and dithiasuccinoyl.

The term "amino acid" as used herein means an organic compound containing both a basic amino group and an acidic carboxyl group. Included within this term are natural amino acids, modified and unusual amino acids, as well as amino acids which are known to occur biologically in free or combined form but usually do not occur in proteins. Included within this term are modified and unusual amino acids, such as those disclosed in, for example, Roberts and Vellaccio (1983) The Peptides, 5: 342-429, the teaching of which is hereby incorporated by reference. Modified or unusual amino acids which can be used to practice the invention include, but are not limited to, D-amino acids, hydroxylysine, 4-hydroxyproline, an N-Cbz-protected amino acid, ornithine, 2,4-diaminobutyric acid, homoarginine, norleucine, N-methylaminobutyric acid, naphthylalanine, phenylglycine, β-phenylproline, tert-leucine, 4-aminocyclohexylalanine, N-methyl-norleucine, 3,4-dehydroproline, N,N-dimethylaminoglycine, N-methylaminoglycine, 4-aminopiperidine-4-carboxylic acid, 6-aminocaproic acid, trans-4-(aminomethyl)-cyclohexanecarboxylic acid, 2-, 3-, and 4-(aminomethyl)-benzoic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclopropanecarboxylic acid, and 2-benzyl-5-aminopentanoic acid.

The term "amino acid residue" as used herein means that portion of an amino acid (as defined herein) that is present in a peptide.

The term "peptide" as used herein means a compound that consists of two or more amino acids (as defined herein) that are linked by means of a peptide bond. The term "peptide" also includes compounds containing both peptide and non-peptide components, such as pseudopeptide or peptide mimetic residues or other non-amino acid components. Such a compound containing both peptide and non-peptide components may also be referred to as a "peptide analog".

The term "peptide bond" means a covalent amide linkage formed by loss of a molecule of water between the carboxyl group of one amino acid and the amino group of a second amino acid.

The term "pharmaceutically acceptable salts" includes acid or base salts of the compounds of formulas (I) and (II). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference. "Prodrugs" are considered to be any covalently bonded carriers which release the active parent drug of formula (I) or (II) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) and (II) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and (II); and the like.

The term "therapeutically effective amount" of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety or depression in a host.

Synthesis

The bicylic fused pyrimidine and pyridines of this invention can be prepared by one of the general schemes outlined below (Scheme 1-9).

Compounds of the Formula (I) wherein X=Y=N and Z=NR³, can be prepared as shown in Scheme 1. ##STR18##

The 4,6-dihydroxypyrimidines (III) can be nitrated using fuming nitric acid and then converted into intermediates (IV) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832). The amino group of pyrimidines of Formula (V) can be prepared from the corresponding nitro compounds (IV) by treatment with reducing agents such as, but not limited to, sodium dithionate, iron or zinc, or catalytic hydrogenation (see: Larock, R. C. Comprehensive Organic Transformations, VCH Publishers, New York, 1989, 411). Reaction with Ar-NH₂ can be used to provide compounds of Formula (VI). Conditions which may facilitate this transformation include the optional presence of protic or aprotic acids, or bases such as alkali metal hydrides, trialkylamines, or alkali metal carbonates, or alkali metal bis(trimethylsilyl)amides wherein the metal can be sodium, lithium, or potassium. These reactions may be conducted neat, or in the optional presence of solvents such as but not limited to cyclic ethers such as tetrahydrofuran, dialkylformamides, ethylene glycol, 2-ethoxyethanol, halocarbons, alkanenitriles, or alkyl alcohols at room temperature or at elevated temperature up to the boiling point of the solvent employed. One skilled in the art of organic synthesis will readily understand the optimal combinations of these conversions to prepare a number of compounds of Formula (VI). Cyclization to triazolopyrimidines of Formula (VII) can then be readily accomplished by diazotization and cyclization of the diamino compounds of Formula (VI) with an alkali metal nitrite in the presence of acid in water with or without an organic cosolvent such as halocarbons, or cyclic ethers. Treatment of compound of Formula (VII) with primary amines then can provide the intermediates (VIII) using reaction conditions similar to those employed for the conversion of (V) to (VI). The rearranged triazolopyrimidine of Formula (IX) may be obtained from the triazolopyrimidine of Formula (VIII) by treatment with base such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides, dialkylacetamides at temperatures ranging from 0° to 200° C. Finally, reaction with an appropriate R⁴ L wherein L is a suitable leaving group such as halo, methanesulfonate, p-toluenesulfonate, or triflate in the presence or absence of bases such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides or dialkylacetamides at temperatures ranging from 0° to 200° C. can be used to generate compounds of Formula (I).

Alternatively, compounds of Formula (I) wherein X=Y=N and Z=NR³, of this invention can be prepared as outlined in Scheme 2: ##STR19## Treatment of compound of Formula (V) with primary amines can provide the diamino substituted pyrimidines (X). Conditions which facilitate this transformation are detailed previously for the conversion of (VII) to (VIII). Cyclization to triazolopyrimidines of Formula (XI) can then be readily accomplished by following the conditions already described for the conversion of (VI) to (VII) in Scheme 1. The leaving group such as, but not limited to, halogen can then be displaced by addition of Ar-NH₂ to provide compounds of Formula (IX) by utilizing the conditions described for the conversion of (V) to (VI). Compounds of Formula (IX) can be converted to (I) in the same way as outlined in Scheme 1.

Compounds of the Formula (VI) can also prepared by an another approach (Scheme 3) involving addition of Ar-NH2 to (IV) to afford compounds of Formula (XII). ##STR20## The nitro group in (XII) can be reduced to give compounds of Formula (VI) under conditions similar to those described for the transformation of (IV) to (V) in Scheme 1. Alternatively, as shown in Scheme 3, addition of Ar-NH₂ to compounds of Formula (IV) can generate in-situ the pyrimidones (XIII). For example, treatment of dichloropyrimidines of Formula (IV) with one equivalent of Ar-NH₂ in the presence of solvents such as (but not limited to) dialkylsulfoxides, dialkylformamides, and alkyl alcohols readily generate pyrimidones (XIII). Compounds of Formula (XIII) can be converted into (IV) by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylanilines with or without an inert solvent. Compounds of Formula (VI) are elaborated to structures of Formula (I) as previously shown in Scheme 1.

Scheme 4 outlines another route to fused triazolopyrimidine type of compounds of this invention. ##STR21## 4,6-dihydroxy-5-nitropyrimidines can be treated with aryl sulfonic anhydrides, aryl sulfonyl chlorides, alkyl sulfonic anhydrides or alkyl sulfonyl chlorides in the presence or absence of bases such as alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in inert solvents such as dialkylformamides, dialkylacetamides at temperatures ranging from 0° to 200° C. to give intermediates of Formula (XIV). Compounds of Formula (XIV) are treated with primary amines to give aminonitropyrimidines (XV). Treatment of (XV) with Ar-NH₂ can provide compounds of Formula (XVI). Compounds of the formula (XVI) can be reduced to amino derivatives (XVII) using the reagents described for the conversion of (IV) to (V) in Scheme 1. Intermediate (XVII) can be converted to a mixture of (VIII) and (IX) by diazotization and cyclization. Compounds of the Formula (VIII) can be converted to (IX) by treatment with base such as but not limited to, alkali metal hydrides, alkaline earth metal hydrides, alkali metal dialkyl amides in an inert solvent. Compounds of Formula (IX) are elaborated to give (I) as delineated in Scheme 1.

Fused imidazolopyrimidines of the Formula (I) wherein X=N, Y=CR², and Z=NR³, can be prepared from compound (X) as shown in Scheme 5. ##STR22## Treatment of (X) with an acylating agent such as, but not limited to, alkyl anhydrides, haloalkyl anhydrides, alkylamides, haloalkyl amides, trialkylorthoesters R² (OR)3 (where R is C₁ -C₄ alkyl) guanidines, cyanogen bromide, R² COOH, urea or thiourea in the presence or absence of an acid (such as HOAc, HC1, H₂ SO₄) in the presence or absence of an organic cosolvent such as alkyl alcohols, cyclic ethers, or aromatic solvents at temperatures ranging from 0° to 200° C. Treatment of (XVIII) with Ar-NH₂ can provide compounds of Formula (XIX). Finally, alkylation of compound (XIX) can provide imidazolopyrimidine (I, wherein X=N, Y=CR², Z=NR³).

The 1,2,3-thiadiazolo[5,4-d]pyrimidines of the formula (I) (wherein X=Y=N and Z=S), can be prepared as shown in Scheme 6. ##STR23##

Compounds of the formula (VII) with thiourea can react upon heating in presence of solvents such as but not limited to, cyclic ethers such as tetrahydrofuran, dialkylformamides such as dimethylformamide, dialkyl acetamides, ethylene glycol, 2-ethoxyethanol, halocarbons such as methylene chloride, alkanenitriles such as acetonitrile, or alkyl alcohols such as methanol, ethanol to give compound (XX) which is alkylated to afford thiadiazolpyrimidine (I) (wherein X=Y=N and Z=S). Compounds of Formula (I) can be converted to sulfoxides as well sulfones under a variety of oxidizing agents such as but not limited to, NaIO₄, KMnO₄ or m-chloroperbenzoic acid.

The method of synthesis of the triazolopyridines of this invention is shown in Scheme 7. ##STR24##

The hydroxy groups in (XXI) can be converted into chloro groups by the action of phosphorous oxychloride with the optional assistance of a catalyst such as dialkylaniline (see: Brown, D. J. et.al. J. Chem. Soc., 1954, 3832) to afford compounds of Formula (XXII). Addition of primary amines to compound (XXII) can provide alkylaminonitropyridines (XXIII). The nitro group in (XXIII) can be reduced using the conditions employed for the transformation of (IV) to (V) to give (XXIV). Diazotization and cyclization of (XXIV) can provide chlorotriazolopyridine derivatives (XXV) as was described for the conversion of (VI) to (VII) in Scheme 1. The chloro group can then be displaced by addition of Ar-NH₂ to afford compounds (XXVI) and then treated with R⁴ L to give (I).

Imidazolopyridines of the present invention can be prepared from compound (XXIV) as shown in Scheme 7 by following the conditions outlined for the conversion of (X) to (XVIII) in Scheme 5. Treatment of compound (XXVII) with Ar-NH₂ using the conditions outlined in Scheme 1 can provide compounds of Formula (I, where R⁴ =H). Alkylation with R⁴ L can afford imidazolopyridines of formula I (where R⁴ is not equal to H).

Alternatively, the triazolopyridines can be synthesized as shown in Scheme 8. ##STR25##

Treatment of compounds of Formula (XXI) with an aliphatic or aromatic amine in the appropriate organic solvent but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF gives the corresponding ammonium salt, which upon treatment with POCl₃ at temperatures from 25 to 120° C., give compounds of Formula (XXVIII). Treatment of compounds of Formula (XXVIII) with appropriate primary amines in an organic solvent such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF, dialkylsulfoxides at temperatures from 25 to 120° C. to give (XXIX). This was converted to (XXIII) by treatment with POC₁₃ at temperatures from 25 to 120° C. Compounds of Formula (XXIII) could be coupled with Ar-NH₂ with or without the presence of solvent at temperatures from 25 to 200° C. to give product (XXX). These could be converted to intermediates (XXXI) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. The final cyclizaton was carried out as described for the conversion of (VI) to (VII) in Scheme 1.

Compounds of general formula (II) may be prepared according to the procedures outlined in Scheme 9. ##STR26##

Intermediates of formula (X), (XV) or (XXIV) may be converted to compounds of formula (XXXIII) by treatment with an acylating agent in the presence or absence of a base in an inert solvent at reaction temperatures ranging from -78° C. to 200° C. Acylating agents include, but are not limited to, phosgene, thiophosgene, diphosgene, triphosgene, carbonyl diimidazole, thiocarbonyl diimidazole, dialkylcarbonates (such as diethyl carbonate) or RaRbN(C=G)ORC (where G=O, S; R^(a), R^(b), and R^(c) are independently C₁ -C₈ alkyl). Bases include, but are not limited to, alkali metal alkoxides, akali metal hydrides, trialkyl amines, pyridine, 4-dimethylaminopyridine, alkali metal dialkyl amides or alkali metal bis(trimethylsilyl)amides. Inert solvents include, but are not limited to, halocarbons, alkanenitriles, dialkylformamides, dialkylacetamides, dialkyl ethers, cyclic ethers such as tetrahydrofuran or dioxane, or alkyl alcohols. Intermediates of (XXXIII) may be converted to compounds of formula (XXXIV) (Formula (II) where R⁴ =H) by reaction with ArNH₂, using the conditions described for the conversion of compound (V) to (VI) in Scheme 1.

Compounds of Formula (XXXV) may be prepared from compounds of structure (XXXIII) by reaction with R¹³ L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases and inert solvents may be the same as those listed above for the preparation of (XXXIII). Intermediates of Formula (XXXV) can be reacted with ArNH₂ to give compounds of formula (XXXVI) (Formula (II), where R⁴ =H) using the conditions described for the conversion of compound (V) to (VI) in Scheme 1. Compounds of Formula (XXXVI) may be converted to compounds of (XXXVII) (Formula (II), where R⁴ does not equal H) by treatment with R⁴ L (where L is a leaving group such as halide, alkanesulfonate or arylsulfonate) in the presence or absence of a base in an inert solvent. Bases and inert solvents may be the same as those listed above for the preparation of (XXXIII).

As illustrated in Scheme 10, treatment of compounds of Formula (XXI) with an aliphatic or aromatic amine in an appropriate organic solvent (such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF) gives the corresponding ammonium salt, which upon treatment with POCl₃ at temperatures from 25 to 120° C., give compounds of Formula (XXVIII). Treatment of compounds of Formula (XXVIII) with appropriate primary amines R³ NH₂ in an organic solvent (such as but not limited to, alkyl alcohols such as methanol, ethanol, propanol, butanol, alkyl alkanoates such as ethyl acetate, alkanenitriles such as acetonitrile, dialkyl formamides such as DMF, dialkylsulfoxides) at temperatures from 25 to 120° C. provides compounds of Formula (XXIX). These can be converted to (XXIII) by treatment with POCl₃ at temperatures from 25 to 120° C. Compounds of Formula (XXIII) can be converted to intermediates (XXIV) by reduction of the nitro group under a variety of reducing conditions, such as those used for the conversion of (IV) to (V) in Scheme 1. Diazotization and cyclization of (XXIV) can provide chlorotriazolopyridine (XXV) as was described for the conversion of of (VI) to (VII) in Scheme I. The chloro group can then be displaced by addition of Ar-NH₂ in the presence of an acid such as but not limited to HCl, H₂ SO₄, AcOH, methanesulfonic acid, p-toluenesulfonic acid in inert solvents such as toluene, xylenes at temperatures ranging from 0° to 200° C. to afford product I. Salts of I are prepared by combining the free base with appropriate acid in a suitable organic solvent. ##STR27##

As shown in Scheme 11, reaction of a 4-amino-3-nitro-pyridone of formula (XXIX) with a reducing agent, such as Na₂ S₂ O₄ affords the corresponding 4-amino-3-amino-pyridone of formula (XXXVII). This transformation can be effected under a variety of reducing conditions, such as catalytic hydrogenation, reducing metal reaction (Fe, Sn, Zn), hydride reaction (NaBH₄, LiAlH₄) etc., which are known to those skilled in the art. The 4-amino-3-amino-pyridone can be converted to the triazolopyridone of formula (XXXVIII) by treatment with an alkali metal nitrite, such as NaNO₂, under acidic conditions. The resulting triazolopyridone can be converted to the corresponding halo-triazolopyridine of formula (XXXIX)(X=Cl, Br), by treatment with a halogenating agent such as POCl₃, PBr₃, POBr₃. Alternatively X can be an appropriate leaving group resulting from treatment of the triazolopyridone with triflic, tosic or mesyl anhydride in the presence of a base. The triazolopyridine can be coupled with arylamines ArNH₂ under acidic, basic or thermal catalysis to compounds of Formula I. ##STR28##

EXAMPLE 1

N-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-3-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: 4,6-Dihydroxy-2-methylpyrimidine (60 g) was added in portions to fuming nitric acid (120 ML) at 0° C. while cooling the reaction flask. After completion of addtion, the reaction was stirred an additional 1 h at 0° C. followed by another 1 h at room temperature. The reaction mixture was then poured over ice (200 g) and the ice was allowed to melt. A light pink solid was isolated by filteration and washed with cold water (100 mL). The solid was dried in a vacuum oven overnight to yield 4,6-dihydroxy-2-methyl-5-nitropyrimidine (72.5 g).

Part B: The product of Part A was added portionwise to phosphorous oxychloride (400 mL) under a nitrogen atmosphere followed by dropwise addition of N,N-diethylaniline (80 mL). The reaction mixture was refluxed for 21/2 h with stirring, cooled to room temperature, poured over ice (2.0 Kg) and stirred for 1 hr. The aqueous layer was extracted with diethyl ether (4×500 mL) and the extracts combined. The combined extracts were washed with brine (500 mL), dried over anhydrous magnesium sulfate, filtered and stripped down to afford 4,6-dichloro-2-methyl-5-nitropyrimidine as a yellow solid (68.8 g) which has an unpleasant odor.

Part C: The product of Part B (42 g) was added to acetic acid (77 mL) and methanol (350 mL). To this mixture was added iron powder (42 g) in portions, stirred for 2 h at 60-65° C., cooled to room temperature, and filtered. The filterate was stripped to a brown solid, which was extracted with ethyl acetate (2×500 mL), washed with 1N NaOH (250 mL), and brine (500 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and stripped down to yield 5-amino-4,6-dichloro-2-methylpyrimidine as a pale yellow solid (25.4 g).

Part D: The product of Part C (14.2 g) and 2-bromo-4-isopropylaniline (17.1 g) were dissolved in 2-ethoxyethanol (60 mL) and refluxed at 135° C. for 30 h. The reaction mixture was cooled, removed the solvent, extracted the residue with dichloromethane, washed with water, dried over anhydrous magnesium sulfate. Filtered the extract, removed the solvent and residue was purified by flash column chromatography on a silica gel using methanol +CH₂ Cl₂ (1:100) to yield 5-amino-4-(2-bromo-4-isopropylphenyl)- amino-6-chloro-2-methylpyrimidine as a cream colored solid (16.05 g).

Part E: The product of Part D (12.5 g) was dissolved in dichloromethane (125 mL) and 50 % aqueous acetic acid (125 mL). To this stirred mixture was added sodium nitrite (2.55 g) in water (10 mL) dropwise at room temperature. After completion of addition, the reaction was stirred for an additional 15 mins. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and stripped down to a residue. The residue was purified by flash column chromatography (CH₂ Cl₂) to afford light brown oil. The oil was crystallized from 1:1 hexane +pentane (15 mL) to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-7-chloro-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine as an off-white solid (12.15 g).

Part F: The product of Part E (0.65 g) was dissolved in dichloromethane (20 mL) and then added 1.0 g of 1-propylamine at room temperature. The reaction mixture was stirred at room temperature for 1 h, washed with water, dried with anhydrous magnesium sulfate, and stripped down to a white solid. The crude solid was recrystallized from 2-propanol (2 mL) to furnish 3-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-N-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white needles (0.58 g; mp 156-157° C.). Elemental analysis for C₁₇ H₂₁ BrN₆ : Theory C: 52.45, H: 5.45, N: 21.59. Found: C: 52.47, H: 5.33, N: 21.46.

Part G: Rearrangement of Product F: The product of Part F (0.40 g) was dissolved in dry DMF (10 mL) and added NaH (0.103 g, 60% in oil) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 14 h and partitioned between ethyl acetate (25 mL) and water (25 mL). The organic layer was washed with brine, dried, and stripped in vacuum to a solid. The solid was recrystallized from 2-propanol (0.5 mL) to afford the title compound as a white crystalline solid (0.35 g; mp 80-81° C.). Elemental analysis for C₁₇ H₂₁ BrN₆ : Theory C: 52.45, H: 5.45, N: 21.59. Found: C: 52.19, H: 5.37, N: 21.48.

EXAMPLE 2

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-5-methyl-3-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The title compound from Example 1 (0.30 g) was dissolved in dry DMF (10 mL) and added NaH (62 mg; 60% in oil) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 5 mins., and then added EtI (0.2 mL) and continued for an additional 24 h. The reaction mixture was partitioned between ethyl acetate (25 mL) and water (25 mL), washed the organic layer with brine, dried, and stripped in vacuum to yield a pale yellow oil. The sample was purified by flash column chromatography (1:100 MeOH +CH₂ Cl₂) to afford the title compound as a colorlesss oil (0.16 g). Elemental analysis for C₁₉ H₂₅ BrN₆ : Theory C: 54.68, H: 6.05 Found: C: 54.66, H: 6.02.

EXAMPLE 3

N-[2-bromo-4-(1-methylethyl)phenyl]-3-butyl-N-ethyl-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was treated with 1-butylamine in the same manner as outlined in Part F to afford 3-[2-bromo-4-(1-methylethyl)phenyl]-N-butyl-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white solid (mp 149-151° C.). Elemental analysis for C₁₈ H₂₃ BrN₆ : Theory C: 53.60, H: 5.76, N: 20.84. Found: C: 53.46, H: 5.62, N: 20.80.

Part B: The product of Part A from Example 3 (0.34 g) was dissolved in dry DMF (10 mL) and added NaH (67 mg; 60% in oil) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 24 h, then added EtI (0.1 mL) and continued for another 24 hrs. The title compound was isolated in the same way as described in Example 2 to afford colorless oil (0.21 g). Elemental analysis for C₂ OH₂₇ BrN₆ : Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.61, H: 6.19, N: 19.23.

EXAMPLE 4

N-[2-bromo-4-(1-methylethyl)phenyl]-3-(cyclopropylmethyl)-N-ethyl-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with aminomethylcyclopropane in the same way as outlined in Part F to furnish 3-[2-bromo-4-(1-methylethyl)phenyl]-N-(cyclopropyl-methyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white needles (mp 166-167° C.). Elemental analysis for C₁₈ H₂₁ BrN₆ : Theory C: 53.87, H: 5.27, N: 20.94. Found: C: 54.11, H: 5.32, N: 21.08.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 4 was rearranged to yield the title compound as a white crystalline solid (mp 100-101° C.). Elemental analysis for C₁₈ H2lBrN6: Theory C: 53.87, H: 5.27, N: 20.94. Found: C: 53.93, H: 5.28, N: 20.78.

Part C: Using the procedure for Example 2, the product of Part B from above was alkylated to furnish the title compound as a colorless oil. Elemental analysis for C₂₀ H₂₅ BrN₆ : Theory C: 55.95, H: 5.88, N: 19.57. Found: C: 56.11, H: 6.04, N: 19.23.

EXAMPLE 5

N-[2-bromo-4-(1-methyl)ethylphenyl]-5-methyl-3-E(1-methoxymethyl)-2-methoxyethyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: Serinol (3.42 g) was added to a solution of trityl chloride (8.36 g) and triethylamine in 75 mL of dry DMF. After stirring at room temperature overnight, the reaction was poured into water and extracted twice with toluene. The combined organic layers were dried over potassium carbonate and concentrated to dryness. Recrystallization from boiling 1:1 benzene/hexane (two crops) afforded N-triphenylmethylserinol (7.59 g).

Part B: Methyl iodide (2.60 mL) was added to a suspension of N-triphenylmethylserinol (6.34 g) and powdered sodium hydroxide (7.60 g) in 95 mL of dry DMSO. After stirring overnight, more methyl iodide was added (0.35 mL). After stirring for an additional 24 h, the reaction was added to water and extracted with toluene, toluene/ether, and then ether. The combined organic layers were dried over potassium carbonate and concentrated to afford 1,3-dimethoxy-2-triphenylmethylaminopropane (7.00 g) as a thick viscous oil.

Part C: To a solution of the product of Part B (1.45 g) in methanol (32 mL) was added 1 M HCl in ether (8.4 mL). After stirring overnight, the reaction was added to hexane and extracted with 1:1 methanol/water. The methanol/water layer was washed twice with hexane and concentrated to dryness to afford 1,3-dimethoxy-2-aminopropane hydrochloride (600 mg) as a waxy solid.

Part D: The product of Part C (576 mg), 3-[2-bromo-4-(1-methyl)ethylphenyl]-7-chloro-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidine (0.733 g, from Example 1, Part E) and triethylamine (0.56 mL) were stirred overnight at room temperature. The reaction mixture was added to aqueous sodium dihydrogen phosphate and extracted three times with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated. Recrystallization from ether/hexane and then boiling methanol afforded N-(1-methoxymethyl-2-methoxyethyl)-3-[2-bromo-4-(1-methyl)ethylphenyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (855 mg) as crystals melting 156.0-158.5°. Calculated for C₁₉ H₂₅ N₆ O₂ Br: C, 50.79%; H, 5.62%; N, 18.70%. Found: C, 50.48%; H, 5.65%; N, 18.41%.

Part E: The product of Part D (449 mg), dry t-butanol (8 mL) and 1 M potassium t-butoxide (2 mL) were heated at reflux for 2 h. The reaction mixture was added to saturated aqueous ammonium chloride and extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate and concentrated to dryness. The residue crystallized after partial evaporation of a dichloromethane/ether/hexane solution, affording the title compound (403 mg) as an amorphorus white solid melting 53.5-60.0°. Calculated for C₁₉ H₂₅ N₆ O₂ Br: C, 50.79%; H, 5.62%; N, 18.70%. Found: C, 50.92%; H, 5.62%; N, 18.77%.

EXAMPLE 6

N-[2-bromo-4-(1-methylethyl)phenyl]-3-(2-methoxyethyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 2-methoxyethylamine in the same way as outlined in Part F to furnish 3-[2-bromo-4-(1-methylethyl)phenyl]-N-(2-methoxyethyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white solid (mp 134-136° C.). Elemental analysis for C₁₇ H2lBrN6O: Theory C: 50.38, H: 5.22, N: 20.74. Found: C: 50.37, H: 5.32, N: 20.52.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 6 was rearranged to yield the title compound as a white crystalline solid (mp 94-95° C.). Elemental analysis for C₁₇ H₂₁ BrN₆ O: Theory C: 50.38, H: 5.22, N: 20.74. Found: C: 50.40, H: 5.31, N: 20.65.

EXAMPLE 7

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-(2-methoxyethyl)-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Using the procedure for Example 2, the product of Part B in Example 6 was alkylated to furnish the title compound as a colorless oil. Elemental analysis for C₁₉ H₂₅ BrN₆ O: Theory C: 52.66, H: 5.81, N: 19.39. Found: C: 52.85, H: 5.96, N: 19.02.

EXAMPLE 8

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-(3-methoxypropyl)-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product of Part E from Example 1 was treated with 3-methoxyethylamine in the same manner as outlined in Part F to afford 3-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-N-(3-methoxypropyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white solid (mp 109-110° C.). Elemental analysis for C₁₈ H₂₃ BrN₆ O: Theory C: 51.56, H: 5.54, N: 20.04. Found: C: 51.57, H: 5.40, N: 20.23.

Part B: The product of Part A from Example 8 was rearranged and alkylated in the same way as outlined in Part B of Example 3 to furnish the title compound as a colorless oil. Elemental analysis for C₂₀ H₂₇ BrN₆ O: Theory C: 53.69, H: 6.08, N: 18.79. Found: C: 53.63, H: 5.98, N: 18.59.

EXAMPLE 9

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product of Part E (0.72 g) from Example 1 was dissolved in a mixture of ethanol (10 mL) and triethylamine (0.21 g) and added 2-amino-1-methoxybutane (0.23 g). The reaction mixture was refluxed for 8 h, removed the solvent, partitioned between ethyl acetate (25 mL) and water (25 mL), washed the organic layer with brine, dried and stripped down to a residue. The residue was purified by flash column chromatography (1:100 MeOH +CH₂ Cl₂) to afford (±)-3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin- 7-amine as a white solid (mp 132-134° C.). Elemental analysis for C₁₉ H₂₅ BrN₆ O: Theory C: 52.66, H: 5.81, N: 19.39. Found: C: 52.52, H: 5.72, N: 19.46.

Part B: The product of Part A from Example 9 was rearranged in a manner similar to Part G of Example 1 to furnish the title compound as a white crystalline solid (mp 115-116° C.). Elemental analysis for C₁₉ H₂₅ BrN₆ O: Theory C: 52.66, H: 5.81, N: 19.39. Found: C: 52.61, H: 5.70, N: 19.41.

EXAMPLE 10

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Using the procedure for Example 2, the product of Part B in Example 9 was alkylated to afford the title compound as a colorless oil. Elemental analysis for C₂₁ H₂₉ BrN₆ O: Theory C: 54.66, H: 6.35, N: 18.21. Found: C: 54.76, H: 6.86, N: 17.85.

EXAMPLE 11

(S)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-(1-methoxymethyl)-2-phenylethyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was treated with S-(+)-2-amino-1-methoxy-3-phenylpropane hydrochloride in the same manner as outlined in Part A of Example 9 to afford (S)-3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-(1-methoxymethyl)-2-phenylethyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white solid (mp 67-69° C.). Elemental analysis for C₂₄ H₂₇ BrN₆ O: Theory C: 58.18, H: 5.49, N: 16.96. Found: C: 57.79, H: 5.39, N: 16.77.

Part B: The product of Part A from Example 11 was rearranged in the same way as outlined in Part G of Example 1 to furnish the title compound as a colorless oil. Elemental analysis for C₂₄ H₂₇ BrN₆ O: Theory C: 58.18, H: 5.49, N: 16.96. Found: C: 57.94, H: 5.49, N: 16.43.

EXAMPLE 12

(S)-methyl 7-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-[2-(methylthio)ethyl]-3H-1,2,3-triazolo[4,5-d] pyrimidine-3-acetate

Part A: The product of Part E from Example 1 was treated with L-methionine methyl ester hydrochloride in the same manner as outlined in Part A of Example 9 to afford (S)-methyl 3-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-[2-(methylthio)ethyl]-3H-1,2,3-triazolo[4,5-d] pyrimidine-7-acetate as a white solid (mp 135-137° C.). Elemental analysis for C₂₀ H₂₅ SBrN₆ O₂ S: Theory C: 48.68, H: 5.12, N: 17.03. Found: C: 48.73, H: 5.21, N: 16.90.

Part B: The product of Part A from Example 12 was rearranged in the same way as described in Part G of Example 1 to furnish the title compound as a colorless oil. Elemental analysis for C₂₀ H₂₅ BrN₆ O₂ S: Theory C: 48.68, H: 5.12, N: 17.03. Found: C: 48.55, H: 5.19, N: 16.82.

EXAMPLE 13

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-ethylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 3-aminoheptane in the same way as outlined in Part F to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-ethylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white crystalline solid (mp 137-138° C.). Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.53, H: 6.54, N: 18.79.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 13 was rearranged to yield the title compound as a colorless oil. Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.78, H: 6.58, N: 18.79.

EXAMPLE 14

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[1-ethylpentyl]-5-methyl-3N-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Using the procedure for Example 2, the product of Part B in Example 13 was alkylated to furnish the title compound as a colorless oil. Mass spec. (ESI): 473.4

EXAMPLE 15

N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-propylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 4-aminoheptane in the same manner as outlined in Part A of Example 9 to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-propylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white crystalline solid (mp 162-163° C.). Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.64, H: 6.56, N: 18.81.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 15 was rearranged to yield the title compound as a white crystalline solid (mp 69-70° C.). Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.69, H: 6.48, N: 18.97.

EXAMPLE 16

N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-butylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 5-aminononane in a manner similar to Part A of Example 9 to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-butylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white crystalline solid (mp 132-133° C.). Elemental analysis for C₂₃ H₃₃ BrN₆ : Theory C: 58.35, H: 7.04, N: 17.75. Found: C: 58.19, H: 7.00, N: 17.97.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 16 was rearranged to yield the title compound as a colorless oil. Elemental analysis for C₂₃ H₃₃ BrN₆ : Theory C: 58.35, H: 7.04, N: 17.75. Found: C: 58.58, H: 7.12, N: 17.47.

EXAMPLE 17

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-ethylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 3-aminohexane in a manner similar to Part A of Example 9 to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-ethylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white crystalline solid (mp 154-155° C.). Elemental analysis for C₂ OH₂₇ BrN₆ : Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.57, H: 6.31, N: 19.41.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 17 was rearranged to yield the title compound as a white crystalline solid (87-88° C.). Elemental analysis for C₂ OH₂₇ BrN₆ : Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 55.70, H: 6.36, N: 19.40.

EXAMPLE 18

(±)-7-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-ethanol

Part A: The product of Part E from Example 1 was treated with DL-2-amino-1-pentanol in a manner similar to Part A of Example 9 to furnish 3-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-ethanol as a white crystalline solid (mp 154-155° C.). Elemental analysis for C₁₉ H₂₅ BrN₆ O: Theory C: 52.66, H: 5.83, N: 19.39. Found: C: 52.54, H: 5.64, N: 19.12.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Examplel8 was rearranged to afford the title compound as a colorless oil. Elemental analysis for C₁₉ H₂₅ BrN₆ O: Theory C: 52.66, H: 5.83, N: 19.39. Found: C: 52.46, H: 5.83, N: 19.18.

EXAMPLE 19

N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-ethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part E from Example 1 was reacted with 3-aminopentane in the same manner as outlined in Part A of Example 9 to yield 3-[2-bromo-4-(1-methylethyl)phenyl]-N-[1-ethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine as a white crystalline solid (mp 171-172° C.). Elemental analysis for C₁₉ H₂₅ BrN₆ : Theory C: 54.68, H: 6.05, N: 20.14. Found: C: 54.54, H: 5.73, N: 20.18.

Part B: Using the procedure for Part G in Example 1, the product of Part A in Example 19 was rearranged to yield the title compound as a white crystalline solid (mp 117-118° C.). Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 54.86, H: 5.93, N: 20.17.

EXAMPLE 20

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[1-ethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Using the procedure for Example 2, the product of Part B in Example 19 was alkylated to afford the title compound as a colorless oil. Elemental analysis for C₂₁ H₂₉ BrN₆ : Theory C: 56.63, H: 6.56, N: 18.87. Found: C: 56.63, H: 6.33, N: 18.78.

EXAMPLE 21

N-(2-bromo-4,6-dimethylphenyl)-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part D (9 g) from Example 1 was dissolved in ethanol (100 mL) and N,N-diisopropylethylamine (8 g). To this mixture 4-aminoheptane (7.65 g) was added and refluxed for 7 days. The ethanol was stripped off in vacuum, the residue was partitioned between ethyl acetate (250 mL) and water (150 mL). The ethyl acetate layer was washed with brine (100 mL), dried and stripped in vacuum to a pale yellow solid. Recrystallized from 2-propanol (20 mL) to yield 5-amino-4-chloro-6-(4-heptyl)amino-2-methylpyrimidine as a white crystalline solid (12.5 g; mpl62-163° C.). Elemental analysis for C₁₂ H₂₁ ClN₄ : Theory C: 56.13, H: 8.24, N: 21.82. Found: C: 55.94 , H: 8.22, N: 21.78.

Part B: Using the procedure for Part E in Example 1, the product of Part A in Example 21 was cyclized to yield 7-chloro-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidine as a pale yellow solid (mp 92-93° C.). Elemental analysis for C₁₂ H₁₈ ClN₅ : Theory C: 53.83, H: 6.79, N: 26.16. Found: C: 53.81, H: 6.60, N: 25.98.

Part C : The product of Part B (0.27 g) from above was combined with 4-bromo-2,6-dimethylaniline (0.2 g) and heated at 150° C. for 4h. The reaction mixture was partitioned between dichloromethane (20 mL) and water (20 mL), washed the organic layer with water, dried and stripped in vacuum to a residue. The residue was purified by flash column chromatography (1:100 MeOH +CH₂ Cl₂) to afford the title compound as an off-white solid (0.26 g; mp 141-142° C.). Elemental analysis for C₂₀ H₂₇ BrN₆ : Theory C: 55.69, H: 6.32, N: 19.48. Found: C: 56.05 , H: 6.26, N: 19.71.

EXAMPLE 22

5-methyl-N-[4-(1-methylethyl)-2-(methylthio)phenyl]-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 21 was treated with 4-isopropyl-2-methylthioaniline in a manner similar to Part C in Example 21, to yield the title compound as a pale yellow oil. Elemental analysis for C₂₂ H₃₂ N₆ S: Theory C: 64.04, H: 7.83, N: 20.37. Found: C: 64.12, H: 7.54, N: 20.41.

EXAMPLE 23

N-[2-bromo-4-(trifluromethyl)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 21 was combined with 2-bromo-4-trifluromethylaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 84-85° C.). Elemental analysis for C₁₉ H₂₂ BrF₃ N₆ : Theory C: 48.42, H: 4.70, N: 17.83. Found: C: 48.58, H: 4.50, N: 17.78.

EXAMPLE 24

N-[2-bromo-4,6-(dimethoxy)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 21 was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 146-147° C.). Elemental analysis for C₂₀ H₂₇ BrN₆ O₂ : Theory C: 51.84, H: 5.87, N: 18.14. Found: C: 51.95, H: 5.68, N: 18.15.

EXAMPLE 25

N-[2, 6-dimethyl-4-(methylthio)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

The product of Part B from Example 21 was combined with 2,6-dimethyl-4-methylthioaniline in a manner similar to Part C in Example 21, to yield the title compound as a cream colored solid (mp 139-140° C.). Elemental analysis for C₂₁ H₃₀ N₆ S: Theory C: 63.28, H: 7.60, N: 21.09. Found: C: 62.98 , H: 7.32, N: 21.38.

EXAMPLE 26

N-(4-acetyl-2-bromophenyl)-3-[1-ethylpropyl]-5-methyl-3H-1,2, 3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part D from Example 1 was treated with 3-aminopentane in a manner similar to Part A of Example 21, to yield 5-amino-4-chloro-2-methyl-6-(3-pentyl)aminopyrimidine as a white crystalline solid (mp 155-156° C.). Elemental analysis for C₁₀ H₁₇ ClN₄ : Theory C: 52.51, H: 7.49, N: 24.50. Found: C: 52.43, H: 7.31, N: 24.59.

Part B: The product of Part A from above was cyclized in a manner similar to Part E of Example 1 to yield 7-chloro-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidine as a white crystalline solid (mp 96-97° C.). Elemental analysis for C₁₀ H₁₄ ClN₅ : Theory C: 50.11, H: 5.90, N: 29.22. Found: C: 50.40, H: 5.78, N: 29.53.

Part C: The product of Part B from above was combined with 4-acetyl-2-bromoaniline in a manner similar to Part C in Example 21, to yield the title compound as a pale yellow solid (mp 153-154° C.). Elemental analysis for C₁₈ H₂₁ BrN₆ O: Theory C: 51.81, H: 5.07, N: 20.14. Found: C: 51.86, H: 5.87, N: 19.84.

EXAMPLE 27

(±)-N-(4-acetyl-2-bromophenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product of Part D from Example 1 was treated with 2-amino-1-methoxybutane in a manner similar to Part A of Example 21, to yield 5-amino-4-chloro-6-(1-methoxy-2-butyl) amino-2-methylpyrimidine as an orange yellow solid (mp 128-130° C.).

Part B: The product of Part A from above was cyclized in a manner similar to Part E of Example 1 to yield 7-chloro-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d] pyrimidine as an off-white crystalline solid (mp 66-87° C.). Elemental analysis for C₁₀ H₁₄ ClN₅ O: Theory C: 46.97, H: 5.53, N: 27.39. Found: C: 47.22 , H: 5.43, N: 27.47.

Part C: The product of Part B from above was combined with 4-acetyl-2-bromoaniline in a manner similar to Part C in Example 21, to yield the title compound as a pale yellow solid (mp 133-134° C.). Elemental analysis for C₁₈ H₂₁ BrN₆ O₂ : Theory C: 49.89, H: 4.90. Found: C: 50.13, H: 4.99.

EXAMPLE 28

(±)-N-(4-bromo-2,6-dimethylphenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 27 was combined with 4-bromo-2,6-dimethylaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 137-138° C.). Elemental analysis for C₁₈ H₂₃ BrN₆ O₂ : Theory C: 51.56, H: 5.54, N: 20.04. Found: C: 51.75, H: 5.43, N: 19.99.

EXAMPLE 29

(±)-N-[2,6-dimethyl-4-(methylthio)phenyl]-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 27 was combined with 2,6-dimethyl-4-methylthioaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 128-129° C.). Elemental analysis for C₁₉ H₂₆ BrN₆ O₅ : Theory C: 59.04, H: 6.78. Found: C: 58.49, H: 6.48.

EXAMPLE 30

(±)-N-(2-bromo-4,6-dimethoxyphenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 27 was treated with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 154-155° C.). Elemental analysis for C₁₈ H₂₃ BrN₆ O₃ : Theory C: 47.90, H: 5.14, N: 18.62. Found: C: 48.28 , H: 5.20, N: 18.91.

EXAMPLE 31

(±)-N-(2-chloro-4,6-dimethoxyphenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product of Part B from Example 27 was treated with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a white crystalline solid (mp 149-150° C.). Elemental analysis for C₁₈ H₂₃ ClN₆ O₃ : Theory C: 53.14, H: 5.70 N: 20.66. Found: C: 53.36, H: 5.72, N: 20.49.

EXAMPLE 32

(±)-3-[1-(1-methoxymethyl) propyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: 4,6-Dichloro-2-methyl-5-nitropyrimidine (10 g, 48 mmol) dissolved in DMSO/water (480 ml/48 ml) followed by addition of 2,4,6-trimethylaniline (7.43 ml, 52.8 mmol) dropwise via syringe over 30 minutes. The reaction was stirred at room temperature for 18 h and filtered. The solid was washed with water until the filtrant volume reached 600 ml. A 150 ml aliquat was removed, diluted with 1.5 liters water, 100 ml saturated brine, and extracted with 4×100 ml methylene chloride. This procedure was repeated until the remainder of the filtrant had been worked up. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in-vacuo. The crude solid was chromatographed on silica gel (350 g, 97/3 methylene chloride/methanol) to give the desired yellow crystalline product, 10.53 g (76%). ¹ H NMR (CDCl₃, 300 MHz) d 12.23 (bs, 1H), 10.60 (S, 1H), 6.95 (s, 2H), 2.34 (2, 3H), 2.33 (s, 3H), 2.16 (s, 6H)

Part B: The product from Part A (3.1 g, 11 mmol) was suspended in phosphorous oxychloride (25 ml) and heated to just under reflux for 1 h, to give a dark homogeneous reaction. The reaction was pipetted slowly and cautiously onto 700 ml ice/water, stirred 30 minutes at room temperature, diluted with 200 ml methylene chloride and transferred to a separatory funnel. The aqueous layer was extracted and reextracted with 3×50 ml methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in-vacuo to constant weight to afford 3.18 g (97%) of the product as a bright yellow solid. ¹ H NMR (CDCl₃, 300 MHz) d 8.79 (bs, 1H), 6.96 (S, 2H), 2.42 (s, 3H), 2.33 (s, 3H), 2.15 (s, 6H).

Part C: The product from Part B (2.73 g, 8.9 mmol) was suspended in 60 ml methanol, followed by addition of acetic acid (3.4 ml), cooling to 0° C. in an ice/acetone bath, and addition of iron (1.84 g). The heterogeneous reaction was stirred 5 minutes at 0° C., then refluxed 3 h, cooled, and filtered through celite. The celite pad was washed with 500 ml ethyl acetate. The dark filtrate was concentrated in-vacuo to near dryness, redissolved in ethyl acetate/water and extracted. The aqueous layer was reextracted several times with ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated in-vacuo. Chromatography on silica gel (300 g, 1/1 ethyl acetate/hexanes) gave the product 2.18 g (88%) as an off-white solid. ¹ H NMR (CDCl₃, 300 MHz) d 6.93 (s, 2H), 6.25 (bs, 1H), 3.13 (bs, 2H), 2.36 (s, 3H), 2.31 (s, 3H), 2.17 (s, 6H).

Part D: The product from Part C (1.28 g, 4.60 mmol) was dissolved in methylene chloride (20 ml), followed by addition of 50% aq. acetic acid (14 ml) and sodium nitrite (338 mg, 4.89 mmol) in water (lml). The reaction was stirred for 3 hours at room temperature, transferred to a separatory funnel, diluted with 100 ml water and 30 ml methylene chloride and extracted. The aqueous layer was reextracted with 3×30 ml methylene chloride. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (200 g, 2/8 ethyl acetate/hexanes) gave the product 1.32 g (88%) as an off-white crystalline solid, mp 186-188° C. CI-HRMS calcd. for C₁₄ H₁₅ N₅ Cl₁ (M+H): 288.1016. Found: 288.1008.

Part E: The product from Part D (425 mg, 1.48 mmol) was treated with triethylamine (0.247 ml, 1.78 mmol) and 2-amino-1-methoxy butane (0.183 ml, 1.78 mmol) in ethanol (10 ml) at reflux for 2 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (150 g, 1/2 hexanes/ethyl acetate) afforded the purified product, 392 mg (75%) as a crystalline solid, mp 156-157.5° C. Anal. Calcd. for C₁₉ H₂₆ N₆ O₁ : C, 64.38; H, 7.39; N, 23.71. Found: C, 64.27; H, 7.47; N, 23.62.

Part F: The product from Part E (250 mg, 0.70 mmol) was treated with sodium hydride (42 mg, 1.40 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 72 hours at room temperature, and 24 h at 50° C., followed by dilution with 100 ml water and extraction with 3×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (50 g, 1/2 hexanes/ethyl acetate) afforded the purified product, 239 mg (96%) as a crystalline solid, mp 144.5-147° C. Anal. Calcd. for C₁₉ H₂₆ N₆ O₁ : C, 64.38; H, 7.39; N, 23.71. Found: C, 64.32; H, 7.33; N, 23.78.

EXAMPLE 33

(±)-N-ethyl-3-[1-(1-methoxy-methyl)propyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-dlpyrimidin-7-amine

The product from Example 32, Part F (125 mg, 0.35 mmol) was treated with sodium hydride (13 mg, 0.42 mmol, 80%) and ethyl iodide (42 ml, 0.42 mmol) in dry dimethylformamide (3 ml) and stirred at room temperature for 48 h. The reaction was diluted with 50 ml water, and extracted with 4×30 ml methylene chloride. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, 3/2 hexanes/ethyl acetate) afforded the desired product, 111 mg (80%) as a clear viscous oil. CI-HRMS calcd. for C₂₁ H₃₁ N₆ O₁ (M+H): 383.2559. Found: 383.2567.

EXAMPLE 34

3-[1-(1-ethyl)propyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product from Example 32, Part D (500 mg, 1.74 mmol) was treated with triethylamine (0.29 ml, 2.09 mmol) and 3-aminopentane (0.243 ml, 2.09 mmol) in ethanol (10 ml) at reflux for 2 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (100 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 462 mg (79%) as a crystalline solid, mp 184.5-186.5° C. Anal. Calcd. for C₁₉ H₂₆ N₆ : C, 67.43; H, 7.74; N, 24.83. Found: C, 67.11; H, 7.59; N, 24.57.

Part B: The product from Part A (300 mg, 0.89 mmol) was treated with sodium hydride (53 mg, 1.78 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 72 hours at 50° C., followed by dilution with 125 ml water and extraction with 3×40 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (75 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 239 mg (80%) as a crystalline solid, mp 160-162° C. Anal. Calcd. for C₁₉ H₂₆ N₆ : C, 67.43; H, 7.74; N, 24.83. Found: C, 67.07; H, 7.85; N, 24.51.

EXAMPLE 35

(±)-3-[1-(1-ethyl)butyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product from Example 32, Part D (525 mg, 1.82 mmol) was treated with triethylamine (0.305 ml, 3.64 mmol) and 3-aminohexane (0.219 ml, 3.64 mmol) in ethanol (8 ml) at 50° C. for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (140 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 450 mg (70%) as a crystalline solid, mp 170.5-172° C. Anal. Calcd. for C₂₀ H₂₈ N₆ : C, 68.15; H, 8.02; N, 23.84. Found: C, 68.10; H, 7.80; N, 23.94.

Part B: The product from Part A (300 mg, 0.85 mmol) was treated with sodium hydride (64 mg, 2.13 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 hours at room temperature, and 24 hours at 50° C., followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (60 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 266 mg (89%) as a crystalline solid, mp 156-157.5° C. Anal. Calcd. for C₁₉ H₂₆ N₆ : C, 68.15; H, 8.01; N, 23.84. Found: C, 68.51; H, 8.10; N, 23.94.

EXAMPLE 36

(±)-3-[1-(1-ethyl)pentyll-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine

Part A: The product from Example 32, Part D (500 mg, 1.74 mmol) was treated with triethylamine (0.290 ml, 4.35 mmol) and 3-aminoheptane (0.343 ml, 4.35 mmol) in ethanol (8 ml) at 50° C. for 18 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (125 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 465 mg (73%) as a crystalline solid, mp 141.5-142.5 C. Anal. Calcd. for C₂₁ H₃₀ N₆ : C, 68.82; H, 8.25; N, 22.93. Found: C, 69.11; H, 8.10; N, 23.04.

Part B: The product from Part A (300 mg, 0.82 mmol) was treated with sodium hydride (49 mg, 1.64 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 hours at 50° C., followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (75 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 236 mg (79%) as a crystalline solid, mp 129-130.5° C. Anal. Calcd. for C₂₁ H₃₀ N₆ : C, 68.82; H, 8.25; N, 22.93. Found: C, 68.73; H, 8.23; N, 22.90.

EXAMPLE 37

5-methyl-3- [1-(1-propyl)butyl]-N-(2,4,6-trimethylphenyl)-3H-1, 2, 3-triazolo [4, 5-d]pyrimidin-7-amine

Part A: The product from Example 32, Part D (255 mg, 0.87 mmol) was treated with triethylamine (0.145 ml, 1.74 mmol) and 4-aminoheptane (0.120 ml, 1.74 mmol) in ethanol (5 ml) at 50° C. for 18 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (60 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 233 mg (73%) as a crystalline solid, mp 145-146.5° C. Anal. Calcd. for C₂₁ H₃₀ N₆ : C, 68.82; H, 8.25; N, 22.93. Found: C, 69.09; H, 8.21; N, 23.04.

Part B: The product from Part A (230 mg, 0.63 mmol) was treated with sodium hydride (47 mg, 1.58 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 hours at room temperature, and 24 h at 50° C., followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (60 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 211 mg (92%) as a crystalline solid, mp 143-144.5° C. Anal. Calcd. for C₂₁ H₃₀ N₆ : C, 68.82; H, 8.25; N, 22.93. Found: C, 69.08; H, 8.10; N, 23.03.

EXAMPLE 38

3-(2-methoxyethyl)-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product from Example 32, Part D (1.07 g, 3.70 mmol) was treated with triethylamine (0.620 ml, 4.44 mmol) and 2-methoxyethylamine (0.386 ml, 4.44 mmol) in ethanol (20 ml) at reflux for 3 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (150 g, 1/1 hexanes/ethyl acetate) afforded the purified product, 1.18 g (97%) as a crystalline solid, mp 141.5-143.5 C. Anal. Calcd. for C₁₇ H₂₂ N₆ O₁ : C, 62.56; H, 6.79; N, 25.75. Found: C, 62.54; H, 6.78; N, 25.70.

Part B: The product from Part A (325 mg, 1.00 mmol) was treated with sodium hydride (60 mg, 2.00 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 72 hours at room temperature, and 24 hours at 50° C., followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (50 g, 1/2 hexanes/ethyl acetate) afforded the purified product, 321 mg (99%) as a crystalline solid, mp 171.5-173.5° C. Anal. Calcd. for C₁₇ H₂₂ N₆ O₁ : C, 62.56; H, 6.79. Found: C, 62.24; H, 6.89.

EXAMPLE 39

N-ethyl-3-(2-methoxyethyl)-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product from Example 38, Part B (150 mg, 0.46 mmol) was treated with sodium hydride (17 mg, 0.55 mmol, 80%) and ethyl iodide (55 ml, 0.69 mmol) in dry dimethylformamide (3 ml) and stirred at room temperature for 48 h. The reaction was diluted with 50 ml water, and extracted with 4-30 ml methylene chloride. The combined organic extracts were dried over anydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (50 g, 1/1 hexanes/ethyl acetate) afforded the desired product, 144 mg (88%) as a clear viscous oil. CI-HRMS calcd. for C₁₉ H₂₇ N₆ O₁ (M+H): 355.2246. Found: 355.2240.

EXAMPLE 40

N-(2-Methyl-4-bromophenyl)-3-[1-(1-propyl)butyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: 4,6-Dichloro-2-methyl-5-nitropyrimidine (5.2 g, 25 mmol) dissolved in DMSO (480 ml) followed by addition of 2-methyl-4-bromoaniline (4.65 g, 25 mmol) dropwise via syringe over 30 minutes. The reaction was stirred at RT for 18 h, followed by addition of 800 ml water. The resulting precipitate was filtered and dried to constant weight affording 7.02 g (83%) of the desired pyrimidone as a yellow solid.

Part B: The product from Part A (6.95 g, 20.5 mmol) was treated with phosphorous oxychloride (120 ml) and brought to reflux for 20 minutes. The reaction was cooled, and slowly quenced on 3 L of ice/water. The resultant precipitate was filtered and dried. Chromatography on silica gel (500 g, 8/2 hexanes/ethyl acetate) gave the purified product, 5.4 g (74%), as a yellow solid.

Part C: The product from Part B (5.4 g, 15.2 mmol) was suspended in 120 ml methanol, followed by addition of acetic acid (6.8 ml), cooling to 0 C in an ice/acetone bath, and addition of iron (4.23 g) under the same conditions described in Example 32, Part C. The resultant brown solid was used directly in the next reaction.

Part D: The product from Part C (15.2 mmol) was dissolved in methylene chloride (100 ml), followed by addition of 50% aq. acetic acid (50 ml) and sodium nitrite (1.15 g, 16.70 mmol) in water (5ml) under the same conditions described in Example 32, Part D. Chromatography of the crude product on silica gel (400 g, 2/8 ethyl acetate/hexanes) gave the product 3.15 g (62% from Part C) as an off-white crystalline solid, mp 145-147.5 C.

Part E: The product from Part D (600 mg, 1.78 mmol) was treated with triethylamine (300 ml, 2.14 mmol) and 4-aminoheptane (246 ml, 2.14 mmol) in ethanol (10 ml) at 50° C. for 18 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (125 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 600 mg (81%) as a crystalline solid, mp 155-156° C. Anal. Calcd. for C₁₉ H₂₅ N₆ Br₁ : C, 54.68; H, 6.05; N, 20.14. Found: C, 54.36; H, 5.71; N, 20.24.

Part F: The product from Part E (350 mg, 0.84 mmol) was treated with sodium hydride (63 mg, 2.10 mmol, 80%) in dry dimethylformamide (5 ml). The reaction was stirred 24 h at room temperature, and 24 h at 50° C., followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (60 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 333 mg (95%) as a crystalline solid, mp 126.5-128° C. Anal. Calcd. for C₁₉ H₂₅ N₆ Br₁ : C, 54.68; H, 6.05; N, 20.14. Found: C, 54.90; H, 6.04; N, 20.40.

EXAMPLE 41

(±)-3-[1-(1-ethyl)butyl]-5-methyl-N-(2-methyl-4-bromophenyl)-3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine

Part A: The product from Example 40, Part D (600 mg, 1.78 mmol) was treated with triethylamine (0.300 ml, 2.14 mmol) and 3-aminohexane (0.214 ml, 2.14 mmol) in ethanol (10 ml) at 50° C. for 18 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (75 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 616 mg (86%) as a crystalline solid, mp 117.5-119.5 C. Anal. Calcd. for C₁₈ H₂₃ N₆ Br₁ : C, 53.60; H, 5.76; N, 20.84. Found: C, 53.53; H, 5.72; N, 20.95.

Part B: The product from Part A (450 mg, 1.12 mmol) was treated with sodium hydride (84 mg, 2.80 mmol, 80%) in dry dimethylformamide (10 ml). The reaction was stirred 72 hours at room temperature, followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (75 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 425 mg (94%) as a crystalline solid, mp 99-101° C.

EXAMPLE 42

(±)-N-(4-bromo-2-methylphenyl)-3-[1-(1-methoxymethyl) propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product from Example 40, Part D (800 mg, 2.37 mmol) was treated with triethylamine (0.400 ml, 2.84 mmol) and 2-amino-1-methoxybutane (0.341 ml, 2.84 mmol) in ethanol (20 ml) at room temperature for 48 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (150 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 697 mg (72%) as a crystalline solid, mp 144.5-146° C. Anal. Calcd. for C₁₇ H₂₁ N₆ Br₁ O₁ : C, 50.38; H, 5.22; N, 20.74. Found: C, 50.35; H, 5.23; N, 20.58.

Part B: The product from Part A (550 mg, 1.36 mmol) was treated with sodium hydride (102 mg, 3.40 mmol, 80%) in dry dimethylformamide (8 ml). The reaction was stirred 72 h at room temperature, followed by dilution with 125 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (75 g, 8/2 hexanes/ethyl acetate) afforded the purified product, 520 mg (94%) as a crystalline solid.

EXAMPLE 43

(±)-3-[1-(1-ethyl)pentyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3R-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: To 2,4-dichloro-2-methyl-5-nitropyrimidine (10.10 g, 48.60 mmol) in dry tetrahydrofuran (200 ml) and triethylamine (6.8 ml, 48.6 mmol) was added 3-amino-2,4,6-trimethylpyridine (3.30 g, 24.3 mmol) in tetrahydrofuran (30 ml) via canulation over 10 minutes at room temperature. The reaction was stirred 72 h, diluted with 1 L of water, and extracted with 4×200 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness in vacuo. Chromatography on silica gel (300 g, 1/1 ethyl acetate/hexanes) afforded the purified product, 4.8 g (64%) as a white solid. ¹ H NMR (300 MHz, CDCl3) d 8.79 (bs, 1H), 6.97 (s, 1H), 2.54 (s, 3H), 2.43 (s, 3H), 2.40 (s, 3H), 2.17 (s, 3H).

Part B: The product from Part A (4.8 g, 15.60 mmol) was treated with iron (4.36 g, 78.00 mmol) in methanol (110 ml) and acetic acid (6 ml) under the same reaction conditions described in Example 32, Part C. Chromatography on silica gel (250 g, 9/1 methylene chloride/methanol) afforded the purified reduction product, 3.1 g, (72%) as a white solid. ¹ H NMR (300 MHz, CDCl₃) d 6.94 (s, 1H), 6.26 (bs, 1H), 3.36 (bs, 1H), 2.52 (s, 3H), 2.41 (s, 3H), 2.35 (s, 3H), 2.16 (s, 3H).

Part C: The product from Part B (2.1 g, 7.56 mmol) was treated with sodium nitrite (574 mg, 8.32 mmol) in methylene chloride (44 ml) and 50% aq. acetic acid (25 ml) under the same reactions conditions described in Example 32, Part D. Chromatography on silica gel (125 g, 1/1 ethyl acetate/hexanes) afforded the purified cyclized product, 1.7 g (78%) as a white solid, mp 204.5-206° C. Anal. Calcd. for C₁₃ H₁₃ N₆ Cl₁ : C, 54.08; H, 4.55; N, 29.11. Found: C, 53.94; H, 4.43; N, 28.79.

Part D: The product from Part C (300 mg, 1.04 mmol) was treated with triethylamine (175 ml, 1.25 mmol) and 3-aminoheptane (243 ml, 1.25 mmol) in ethanol (10 ml) at reflux for 2.5 hours. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (20 g, 1/2 hexanes/ethyl acetate) afforded the purified product, 356 mg (93%) as a crystalline solid, mp 122-130° C. Anal. Calcd. for C₂₀ H₂₉ N₇ : C, 65.37; H, 7.95; N, 26.68. Found: C, 65.35; H, 7.95; N, 26.82.

Part E: The product from Part D (160 mg, 0.44 mmol) was treated with sodium hydride (27 mg, 0.88 mmol, 80%) in dry dimethylformamide (4 ml). The reaction was stirred 24 hours at room temperature, and 100 hours at 50° C., followed by dilution with 100 ml water and extraction with 3×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Preparative HPLC [(25-65%) acetonitrile : trifluoroacetic acid/water:trifluoroacetic acid, Dynamax C₁₈ column] afforded the purified product, 60 mg (38%) as an amorphous foam. CI-HRMS calcd. for C₂₀ H₂₉ N₇ (M+H): 368.2545. Found: 368.2563.

EXAMPLE 44

(±)-N-ethyl-3-[1-(1-ethyl) pentyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product from Example 43, Part E (29 mg, 0.08 mmol) was treated with sodium hydride (3 mg, 0.1 mmol, 80%) and ethyl iodide (9.6 ml, 0.12 mmol) in dry dimethylformamide (1 ml) and stirred at room temperature for 168 h. The reaction was diluted with 10 ml water, and extracted with 4×5 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (10 g, 1/1 hexanes/ethyl acetate) afforded the desired product, 19.7 mg (63%) as a clear viscous oil. CI-HRMS calcd. for C₂₂ H₃₃ N₇ (M+H): 396.2876. Found: 396.2876.

EXAMPLE 45

(±)-3-[1-(1-ethyl)butyl]-5-methyl-N-[(2,4,6-trimethyl)3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: The product from Example 43, Part C (546 mg, 1.89 mmol) was treated with triethylamine (0.316 ml, 2.27 mmol) and 3-aminohexane (0.210 mg, 2.07 mmol) in ethanol (15 ml) at reflux for 2.5 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (50 g, ethyl acetate) afforded the purified product, 530 mg (79%) as a crystalline solid, mp 155.5-158° C. Anal. Calcd. for C₁₉ H₂₇ N₇ : C, 64.56; H, 7.71; N, 27.74. Found: C, 64.59; H, 7.62; N, 27.91.

Part B: The product from Part A (400 mg, 1.13 mmol) was treated with sodium hydride (94 mg, 3.11 mmol, 80%) in dry dimethylformamide (12 ml). The reaction was stirred 72 h at 50° C., followed by dilution with 100 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (50 g, 1/3 hexanes/ethyl acetate) afforded the purified product, 355 mg (89%) as a crystalline solid, mp 132-140.5 C. Anal. Calcd. for C₁₉ H₂₇ N₇ : C, 64.56; H, 7.71; N, 27.74. Found: C, 64.52; H, 7.58; N, 27.97.

EXAMPLE 46

N-ethyl-3-[1-(1-ethyl)butyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product from Example 45, Part B (250 mg, 0.71 mmol) was treated with sodium hydride (26 mg, 0.85 mmol, 80%) and ethyl iodide (0.85 ml, 1.07 mmol) in dry dimethylformamide (7 ml) and stirred at room temperature for 15 h. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 221 mg (81%) as a clear viscous oil.

EXAMPLE 47

3-[1-(1-propyl)butyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d] pyrimidin-7-amine

Part A: The product from Example 43, Part C (700 mg, 2.42 mmol) was treated with triethylamine (0.405 ml, 2.91 mmol) and 4-aminoheptane (335 mg, 2.91 mmol) in ethanol (20 ml) at reflux for 2.5 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (50 g, 1/3 exanes/ethyl acetate) afforded the purified product, 845 mg (96%) as a crystalline solid, mp 135.5-137.5° C. Anal. Calcd. for C₂₀ H₂₉ N₇ : C, 65.37; H, 7.95; N, 26.68. Found: C, 65.71; H, 7.70; N, 26.95.

Part B: The product from Part A (600 mg, 1.63 mmol) was treated with sodium hydride (147.5 mg, 4.89 mmol, 80%) in dry dimethylformamide (15ml). The reaction was stirred 15 h at 50° C., followed by dilution with 200 ml water and extraction with 5×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (50 g, 1/3 hexanes/ethyl acetate) afforded the purified product, 560 mg (93%) as a crystalline solid, mp 128-130° C. CI-HRMS calcd. for C₂₀ H₂₉ N₇ (M+H): 368.2561. Found: 368.2563.

EXAMPLE 48

N-ethyl-3-[1-(1-propyl) butyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-l,2,3-triazolo[4,5-d]pyrimidin-7-amine

The product from Example 47, Part B (400 mg, 1.09 mmol) was treated with sodium hydride (40 mg, 1.31 mmol, 80%) and ethyl iodide (0.130 ml, 1.63 mmol) in dry dimethylformamide (10 ml) and stirred at room temperature for 15 hours. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/3 hexanes/ethyl acetate) afforded the desired product, 373 mg (87%) as a clear viscous oil.

EXAMPLE 49

(±)-3-[1-(1-methoxymethyl) propyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo [4, 5-d]pyrimidin-7-amine

Part A: The product from Example 43, Part C (700 mg, 2.42 mmol) was treated with triethylamine (0.405 ml, 2.91 mmol) and 2-aminomethoxybutane (0.350 ml, 2.91 mmol) in ethanol (20 ml) at reflux for 2.5 h. The reaction was concentrated directly to dryness in vacuo. Chromatography on silica gel (50 g, 1/1 hexanes/tetrahydrofuran) afforded the purified product, 845 mg (98%) as a crystalline solid, mp 132-136.5° C. Anal. Calcd. for C₁₈ H₂₅ N₇ O₁ : C, 60.82; H, 7.1; N, 27.58. Found: C, 61.13; H, 6.89; N, 27.54.

Part B: The product from Part A (600 mg, 1.68 mmol) was treated with sodium hydride (151.2 mg, 5.04 mmol, 80%) in dry dimethylformamide (15ml). The reaction was stirred 15 hours at 50° C., followed by dilution with 100 ml water and extraction with 4×30 ml ethyl acetate. The combined organics were dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. Chromatography on silica gel (50 g, 1/1 hexanes/tetrahydrofuran) afforded the purified product, 500 mg (83%) as a crystalline solid, mp 141.5-144° C. Anal. Calcd. for C₁₈ H₂₅ N₇ O₁ : C, 60.82; H, 7.1; N, 27.58. Found: C, 60.94; H, 6.95; N,27.46.

EXAMPLE 50

(±)-N-ethyl-3-[1-(1-methoxy methyl)propyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-dlpyrimidin-7-amine

The product from Example 49, Part B (350 mg, 0.99 mmol) was treated with sodium hydride (36 mg, 1.19 mmol, 80%) and ethyl iodide (0.119 ml, 1.49mmol) in dry dimethylformamide (10 ml) and stirred at room temperature for 15 h. The reaction was diluted with 150 ml water, and extracted with 3×30 ml ethyl acetate. The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to dryness. Chromatography on silica gel (20 g, 1/1 hexanes/tetrahydrofuran) afforded the desired product, 338 mg (89%) as a clear viscous oil.

EXAMPLE 51

N-(2,4-dibromophenyl)-5-methyl-3-(1-propyl)butyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: 4-Aminoheptane (2.5 g) was added to a solution of 4,6-ditosyloxy-2-methyl-5-nitropyrimidine (10.5 g) and N,N-diisopropylethylamine (3.8 mL) in dichloromethane (219 mL). The reaction was stirred under nitrogen for 5 h at room temperature and then extracted with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated to yield N-(1-propyl)butyl-2-methyl-5-nitro-4-tosyloxypyrimidin-6-amine as a pale yellow solid (9.1 g)

Part B: The product of part A (9.0 g), anhydrous toluene (200 mL), N,N-diisopropylethylamine (3.8 mL) and 2,4-dibromoaniline (5.5 g) were heated at 65° C. for 16 h under nitrogen. The reaction was added to saturated aqueous NH₄ Cl and extracted with dichloromethane (3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to yield N-4-(2,4-dibromophenyl)-N-[6-(1-propyl)butyl]-2-methyl-5-nitro-pyrimidin-4,6-diamine as a yellow solid (6.5 g).

Part C: The product of part B (6.5 g), 1,4-dioxane (65 mL), water (65 mL), sodium dithionite (18.0 g) and 40% ammonium hydroxide (6.5 mL) were stirred for 3 h at room temperature. The reaction mixture was added to saturated aqueous NH₄ Cl and extracted with ethyl acetate (3 times). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using EtOAc/hexane (2:8) to yield N-[4-(2,4-dibromophenyl)]-N-[6-(1-propyl)butyl]-2-methyl-5-aminopyrimidin-4,6-diamine as a pale yellow solid (5.1 g).

Part D: The product of part C (5.0 g) was dissolved in a 2:1:1 mixture of dichloromethane, acetic acid and water. To this solution was added sodium nitrite (0.9 g) and the resulting solution was stirred for 2 h at room temperature. The reaction was added to an equal volume of water and extracted with dichloromethane (3 times). The combined organic layers were washed with saturated aqueous NaHCO₃, then were dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (2:8) to yield N-(l-propyl)butyl-3-(2,4-dibromophenyl)-5-methyl-3H-1,2,3- triazolo[4,5-d] pyrimidin-7-amine as a white solid (3.9 g). A small amount of the title compound, N-(2,4-dibromophenyl)-5-methyl-3-(1-propyl)butyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (0.18 g) was also isolated from the chromatography.

Part E: Sodium hydride (0.24 g) was added to a solution of the product of part D (3.9 g) in anhydrous DMF (82 mL). The resulting solution was stirred for 16 h under nitrogen and the partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated. The resulting solid was recrystallized from boiling 2-propanol to afford the title compound as a white crystalline solid (3.6 g).

EXAMPLE 52

N-[4-acetyl-2-bromophenyl]-5-methyl-3-(1-propyl)butyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Bis(triphenylphosphine)palladium dichloride (11.9 mg), tetrakis(triphenylphosphine)palladium (19.6 mg) and 1-ethoxyvinyltributyltin (299 mg) were added to the product of Part E, from Example 51 (0.33 g) dissolved in toluene (5 mL). The reaction was heated to reflux and stirred overnight. The solvent was then removed under vacuum and the residue partitioned between ether and aqueous saturated NaF. The mixture was then filtered and separated. The organic layer was then washed with 1N HC₁, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using ethyl acetate/hexane (2:8) to yield the title compound.

EXAMPLE 53

N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-(N,N-dimethylamino-methyl)butyl] -5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine

Part A: A solution of N-CBZ-d, 1-norvaline (TCI America) in THF (0.5 M) is treated in sequence with 1-hydroxybenzotriazole hydrate (1.2 eq), dimethylamine hydrochloride (1.3 eq), triethylamine (1.4 eq), and dicyclohexylcarbodiimide (1.2 eq). After stirring overnight, the mixture is filtered, which is followed by aqueous workup and chromatography, to afford N,N-dimethyl-N'-CBZ-d,l-norvalinamide, as an oil (TLC Rf=0.10, 30:70 ethyl acetate-hexane).

Part B: A solution of the CBZ compound from Part A above is dissolved in methanol (1 M), and 5% Pd on carbon is added. The mixture is submitted to hydrogenation in the usual Parr shaker apparatus (50 PSI, overnight). The resulting mixture is filtered through celite and evaporated to afford sufficiently pure product, N,N-dimethyl-d,l-norvalinamide, as an oil (TLC baseline in 30:70 ethyl acetate-hexane).

Part C: The amine from Part B is elaborated to title compound by using the procedure outlined in Example 32 or 51. Spectral data. ¹ H NMR (300 MHz, CDCl₃): d 8.61 (1H, d, J =8.4 Hz), 8.20 (1H, br s), 7.48 (1H, d, J =1.8 Hz), 7.26 (1H, dd, J =8.4, 1.8 Hz), 5.08-4.98 (1H, m), 3.27 (1H, dd, J =12.6, 9.7 Hz), 2.91 (1H, heptet, J=7.0 Hz), 2.68 (3H, s), 2.67 (1H, dd, J=12.6 Hz), 2.22 (6H, s), 2.21-2.11 (1H, m), 1.99-1.89 (1H, m), 1.29-1.19 (1H, m), 1.27 (6H, d, J=7.0 Hz), 1.16-1.05 (1H, m), 0.88 (3H, t, J=7.1 Hz). MS(NH₃ -CI): m/e 464 (3), 463 (25), 462 (100), 461 (29), 460 (98).

The compounds of Examples 54-208 can be made by the methods exemplified in Examples 1-53.

                  TABLE 1                                                          ______________________________________                                         3H-1,2,3-triazolo[4,5-d]pyrimidines:                                            ##STR29##                                                                     Ex                                                                             No.   Ar              R.sup.3         R.sup.4                                  ______________________________________                                          54   2-Br-4-i-Pr-Ph  C(Me).sub.2 CH.sub.2 --OCH.sub.3                                                               H                                         55   2-Br-4-i-Pr-Ph  cyclopentyl     H                                         56   2-Br-4,6-(OMe).sub.2 -Ph                                                                       CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         57   2-Cl-4,6-(OMe).sub.2 -Ph                                                                       CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         58   4-i-Pr-2-SMe-Ph CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         59   4-i-Pr-2-SO.sub.2 Me-Ph                                                                        CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         60   4-(COMe)-2-Br-Ph                                                                               CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         61   2-Br-4-CF.sub.3 -Ph                                                                            CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         62   4-Br-2,6-(Me).sub.2 -Ph                                                                        CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         63   2,6-(Me).sub.2 -4-SO.sub.2 Me-Ph                                                               CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         64   2,4,6-(Me).sub.3 Ph                                                                            CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         65   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         66   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         67   4-Br-2-Me-Ph    CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         68   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         69   4-I-2-Me-Ph     CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         70   2-I-4-i-Pr-Ph   CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         71   2-Br-4-SMe-Ph   CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         72   2-Br-4-SO.sub.2 Me-Ph                                                                          CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         73   2-Br-4-N(Me).sub.2 -6-OMe-Ph                                                                   CH(Bz)CH.sub.2 --OCH.sub.3                                                                     H                                         74   2-Br-4,6-(OMe).sub.2 -Ph                                                                       CH(Et)Bu.sup.n  H                                         75   2-Cl-4,6-(OMe).sub.2 -Ph                                                                       CH(Et)Bu.sup.n  H                                         76   4-i-Pr-2-SMe-Ph CH(Et)Bu.sup.n  H                                         77   4-i-Pr-2-SO.sub.2 Me-Ph                                                                        CH(Et)Bu.sup.n  H                                         78   4-(COMe)-2-Br-Ph                                                                               CH(Et)Bu.sup.n  H                                         79   2-Br-4-CF.sub.3 -Ph                                                                            CH(Et)Bu.sup.n  H                                         80   4-Br-2,6-(Me).sub.2 -Ph                                                                        CH(Et)Bu.sup.n  H                                         81   2,6-(Me).sub.2 -4-SO.sub.2 Me-Ph                                                               CH(Et)Bu.sup.n  H                                         82   2,6-(Me).sub.2 -4-SMe-Ph                                                                       CH(Et)Bu.sup.n  H                                         83   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(Et)Bu.sup.n  H                                         84   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(Et)Bu.sup.n  H                                         85   4-Br-2-Me-Ph    CH(Et)Bu.sup.n  H                                         86   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(Et)Bu.sup.n  H                                         87   4-I-2-Me-Ph     CH(Et)Bu.sup.n  H                                         88   2-I-4-i-Pr-Ph   CH(Et)Bu.sup.n  H                                         89   2-Br-4-SO.sub.2 Me-Ph                                                                          CH(Et)Bu.sup.n  H                                         90   2-Br-4-N(Me).sub.2 -6-OMe-Ph                                                                   CH(Et)Bu.sup.n  H                                         91   2,4-[SMe].sub.2 -Ph                                                                            CH(Et)Bu.sup.n  H                                         92   2,4-[SO.sub.2 Me].sub.2 -Ph                                                                    CH(Et)Bu.sup.n  H                                         93   2-Br-4,6-(OMe).sub.2 -Ph                                                                       CH(Et)Pr.sup.n  H                                         94   2-Cl-4,6-(OMe).sub.2 -Ph                                                                       CH(Et)Pr.sup.n  H                                         95   4-i-Pr-2-SMe-Ph CH(Et)Pr.sup.n  H                                         96   4-i-Pr-2-SO.sub.2 Me-Ph                                                                        CH(Et)Pr.sup.n  H                                         97   4-(COMe)-2-Br-Ph                                                                               CH(Et)Pr.sup.n  H                                         98   4-Br-2-CF.sub.3 -Ph                                                                            CH(Et)Pr.sup.n  H                                         99   4-Br-2,6-(Me).sub.2 -Ph                                                                        CH(Et)Pr.sup.n  H                                        100   2,6-(Me).sub.2 -4-SMe-Ph                                                                       CH(Et)Pr.sup.n  H                                        101   2,6-(Me).sub.2 -4-SO.sub.2 Me-Ph                                                               CH(Et)Pr.sup.n  H                                        102   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(Et)Pr.sup.n  H                                        103   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(Et)Pr.sup.n  H                                        104   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(Et)Pr.sup.n  H                                        105   2-I-4-i-Pr-Ph   CH(Et)Pr.sup.n  H                                        106   2-Br-4-SMe-Ph   CH(Et)Pr.sup.n  H                                        107   2-Br-4-SO.sub.2 Me-Ph                                                                          CH(Et)Pr.sup.n  H                                        108   2-Br-4,6-(OMe).sub.2 -Ph                                                                       CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        108   (m.p. 163-165° C.)                                                109   2-Cl-4,6-(OMe).sub.2 -Ph                                                                       CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        109   (m.p. 166-167° C.)                                                110   4-i-Pr-2-SMe-Ph CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        110   (m.p. 89-90° C.)                                                  111   4-i-Pr-2-SO.sub.2 Me-Ph                                                                        CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        112   4-(COMe)-2-Br-Ph                                                                               CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        113   2-Br-4-CF.sub.3 -Ph                                                                            CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        114   4-Br-2,6-(Me).sub.2 -Ph                                                                        CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        114   (m.p. 160-162° C.)                                                115   2,6-(Me).sub.2 -4-SMe-Ph                                                                       CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        116   2,6-(Me).sub.2 -4-SO.sub.2 Me-Ph                                                               CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        117   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        118   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        119   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        120   4-I-2-Me-Ph     CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        121   2-I-4-i-Pr-Ph   CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        122   2-Br-4-SMe-Ph   CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        123   2-Br-4-SO.sub.2 Me-Ph                                                                          CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        124   2-Br-4-N(Me).sub.2 -6-OMe-Ph                                                                   CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        125   2,4-[S(O).sub.2 Me].sub.2 -Ph                                                                  CH(C.sub.2 H.sub.5).sub.2                                                                      H                                        126   2-Cl-4,6-(OMe).sub.2 -Ph                                                                       CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        127   4-i-Pr-2-S(O).sub.2 Me-Ph                                                                      CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        128   4-(COMe)-2-Br-Ph                                                                               CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        129   4-Br-2-CF.sub.3 -Ph                                                                            CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        130   4-Br-2,6-(Me).sub.2 -Ph                                                                        CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        131   2,6-(Me).sub.2 -4-S(O).sub.n Me-Ph                                                             CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        132   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        133   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        134   4-Cl-2-Me-Ph    CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        135   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        136   4-I-2-Me-Ph     CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        137   2-I-4-i-Pr-Ph   CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        138   2-Br-4-N(Me).sub.2 -6-OMe-Ph                                                                   CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        139   2,4-[SMe].sub.2 -Ph                                                                            CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        140   2,4-[S(O)Me].sub.2 -Ph                                                                         CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        141   2,4-[S(O).sub.2 Me].sub.2 -Ph                                                                  CH(n-C.sub.3 H.sub.7).sub.2                                                                    H                                        142   4-i-Pr-2-S(O).sub.n Me-Ph                                                                      CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        143   2-Br-4-CF.sub.3 -Ph                                                                            CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        144   2,6-(Me).sub.2 -4-S(O)Me-Ph                                                                    CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        145   2,6-(Me).sub.2 -4-S(O).sub.2 Me-Ph                                                             CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        146   2,6-(Me).sub.2 -4-CF.sub.3 -Ph                                                                 CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        147   2,6-(Et).sub.2 -4-Br-Ph                                                                        CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        148   2-Br-4,6-(Me).sub.2 -Ph                                                                        CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        148   (m.p. 156-157° C.)                                                149   4-Cl-2-Me-Ph    CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        150   4-N(Et).sub.2 -2-Me-Ph                                                                         CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        151   4-I-2-Me-Ph     CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        151   (m.p. 122-123° C.)                                                152   2-I-4-i-Pr-Ph   CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        153   2-Br-4-SMe-Ph   CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        154   2-Br-4-S(O).sub.2 Me-Ph                                                                        CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        155   2-Br-4-NMe.sub.2 -Ph                                                                           CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        156   2-Me-4-NMe.sub.2 -Ph                                                                           CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        156   (m.p. 159-162° C.)                                                157   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        158   2-Br-4-OMe-Ph   CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        159   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        160   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        161   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        162   2-MeS(O).sub.2 -4,6-(Me).sub.2 -Ph                                                             CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        163   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(Et)CH.sub.2 --OCH.sub.3                                                                     H                                        164   2-Br-4-NMe.sub.2 -Ph                                                                           CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       165   2-Me-4-NMe.sub.2 -Ph                                                                           CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       166   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       167   2-Br-4-OMe-Ph   CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       168   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       169   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       170   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       171   2-MeS(O).sub.2 -4,6-(Me)2-Ph                                                                   CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       172   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(Et)CH.sub.2 --OCH.sub.3                                                                     Et                                       173   2-Br-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        174   2-Me-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        175   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        176   2-Br-4-OMe-Ph   CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        177   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        178   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        179   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        180   2-MeS(O).sub.2 -4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        181   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 H                                        182   2-Br-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       183   2-Me-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       184   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       185   2-Br-4-OMe-Ph   CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       186   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       187   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       188   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       189   2-MeS(O).sub.2 -4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       190   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --OCH.sub.3).sub.2                                                                 Et                                       191   2-Br-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        192   2-Me-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        193   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        194   2-Br-4-OMe-Ph   CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        195   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        196   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(CH.sub.2 --CH.sub.2 --CH.sub.3)                                                             H                                        197   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        198   2-MeS(O).sub.2 -4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        199   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       H                                        200   2-Br-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       201   2-Me-4-NMe.sub.2 -Ph                                                                           CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       202   2,6-(Me).sub.2 -4-NMe.sub.2 -Ph                                                                CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       203   2-Br-4-OMe-Ph   CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       204   2-N(Me).sub.2 -4-Me-Ph                                                                         CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       205   2-MeS-4,6-(Me).sub.2 -Ph                                                                       CH(CH.sub.2 --CH.sub.2 --CH.sub.3)                                                             Et                                       206   2-MeS(O)-4,6-(Me).sub.2 -Ph                                                                    CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       207   2-MeS(O).sub.2 -4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       208   2-(CH.sub.3 CO)-4,6-(Me).sub.2 -Ph                                                             CH(CH.sub.2 --CH.sub.2 --CH.sub.3).sub.2                                                       Et                                       ______________________________________                                    

EXAMPLE 209

N-[2-bromo-4-(1-methylethyl)phenyl]-2-methyl-9-(1-propylbutyl)-9H-purin-6-amine

Part A: The product of Part A (0.74 g) from Example 21 was treated with triethyl orthoformate (7.68 g) and con. H₂ SO₄ (3 drops) and heated to 100° C. for 4h. The excess triethyl orthoformate was removed in vacuum, and the residue was purified by flash column chromatography to yield 6-chloro-2-methyl-9-(1-propylbutyl)-9H-purine as a colorless liquid (0.32 g).

Part B: The product of Part A from above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C of Example 21 to afford the title compound as a brown oil. Elemental analysis for C₂₂ H30BrN5: Theory C: 59.46, H: 6.80 N: 15.76. Found: C: 59.56, H: 6.83, N: 15.67.

EXAMPLE 210

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-9-(1-ethylpentyl)-2-methyl-9H-purin-6-amine

Part A: The product of Part D from Example 1 was treated with 3-aminoheptane in a manner similar to Part A of Example 21, to yield 5-amino-4-chloro-6-(3-heptyl)amino-2-methylpyrimidine as a white crystalline solid (mp 116-117° C.). Elemental analysis for C₁₂ H₂₁ ClN₄ : Theory C: 56.13, H: 8.24, N: 21.82. Found: C: 56.16, H: 8.26, N: 21.82

Part B: The product of Part A from above was treated with triethyl orthoformate in a manner similar to Part A of Example 209 to yield 6-chloro-9-(1-ethylpentyl)-2-methyl-9H-purine as a pale yellow liquid.

Part C: The product of Part B from above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C of Example 21 to afford the title compound as a colorless oil. Elemental analysis for C₂₂ H₃₀ BrN₅ : Theory C: 59.46, H: 6.80 N: 15.76. Found: C: 59.30, H: 6.82, N: 15.50.

EXAMPLE 211

(±)-N-[2-bromo-4-(trifluromethyl)phenyl]-9-[1-(methoxymethyl)propyl]-2-methyl-9H-purin-6-amine

Part A: The product of Part A from Example 27 was treated with triethyl orthoformate in a manner similar to Part A of Example 209 to yield 6-chloro-9-[1-(methoxymethyl)propyl]-2-methyl-9H-purine as a white crystalline solid (mp 105-106° C.). Elemental analysis for C₁₁ H₁₅ ClN₄ O: Theory C: 51.87, H: 5.95 N: 22.00. Found: C: 51.85, H: 5.81, N: 21.96.

Part B: The product of Part A from above was combined with 2-bromo-4-trifluromethylaniline in a manner similar to Part C of Example 21 to afford the title compound as a off-white solid (mp 123-124° C.). Elemental analysis for C₁₈ H₁₉ BrF₃ N₅ O: Theory C: 47.18, H: 4.19, N: 15.28. Found: C: 47.28, H: 3.97, N: 15.50.

The compounds of Examples 212-217 can be made by methods exemplified in Examples 209-211.

                  TABLE 2                                                          ______________________________________                                         9H-imidazo[4,5-d]pyrimidines:                                                   ##STR30##                                                                     Ex.                                                                            No.     Ar            R.sup.2                                                                               R.sup.3   R.sup.4                                 ______________________________________                                         212     2-Br-4-i-Pr-Ph                                                                               Me     CH(n-C.sub.3 H.sub.7).sub.2                                                              H                                       213     2,4,6-(Me).sub.3 -Ph                                                                         Me     CH(n-C.sub.3 H.sub.7).sub.2                                                              H                                       214     4-Br-2,6-(Me).sub.2 -Ph                                                                      Me     CH(n-C.sub.3 H.sub.7).sub.2                                                              H                                       215     2-Br-4-i-Pr-Ph                                                                               Me     CH(Et)CH.sub.2 OCH.sub.3                                                                 H                                       216     2,4,6-(Me).sub.3 -Ph                                                                         Me     CH(Et)CH.sub.2 OCH.sub.3                                                                 H                                       217     4-Br-2,6-(Me).sub.2 -Ph                                                                      Me     CH(Et)CH.sub.2 OCH.sub.3                                                                 H                                       ______________________________________                                    

EXAMPLE 218

N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-5-methyl-[1,2,3]thiadiazolo[5,4-dlpyrimidin-7-amine

Part A: The product of Part E (1.1 g) from Example 1 was dissolved in ethanol (15 mL) and added thiourea (0.27 g). The reaction mixture was refluxed for lh, removed the solvent in vacuum, partitioned between CH₂ Cl₂ and water, washed with brine, dried and stripped down to a residue. The residue was purified by flash column chromatography (CH₂ Cl₂) to furnish the title compound as a white crystalline solid (1.01 g, mp 81-82° C.). Elemental analysis for C₁₄ H₁₄ BrN₅ S: Theory C: 46.16, H: 3.87, N: 19.23, S: 8.80. Found: C: 46.15, H: 3.85, N: 19.09, S: 8.60.

Part B: Using the procedure for Example 2, the product of Part A was alkylated to afford the title compound as a pale yellow oil. Elemental analysis for C₁₆ H₁₈ BrN₅ S: Theory C: 48.98, H: 4.62, N: 17.85. Found: C: 49.23, H: 4.71, N: 17.72.

The compounds of Examples 219 and 220 can be made by the method of Example 218.

                  TABLE 3                                                          ______________________________________                                         [1,2,3]-Thiadiazolo[5,4-d]pyrimidines:                                          ##STR31##                                                                     Ex.                                                                            No.      Ar            Z       R.sup.4                                         ______________________________________                                         219      2-Br-4-i-Pr-Ph                                                                               S       n-C.sub.3 H.sub.7                               220      2-Br-4-i-Pr-Ph                                                                               S       CH.sub.2 --CH═CH.sub.2                      ______________________________________                                    

EXAMPLE 221

N-[2-bromo-4-(1-methylethyl)phenyl]-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

Part A: 2,4-Dihydroxy-6-methyl-3-nitropyridine was added to phosphorous oxychloride in a manner similar to Part B of Example 1 to afford 2,4-dichloro-3-nitro-6-methylpyridine as a pale yellow solid (mp 69-70° C.).

Part B: The product of Part A (10.35 g) from above was dissolved in ethanol (100 mL) and then added triethylamine (5.05 g) followed by 3-aminopentane at room temperature under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 4 days, ethanol was removed in vacuum, the residue was partitioned between ethyl acetate (150 mL) and water (150 mL). The organic layer was washed with brine, dried, stripped down to a residue and purified by flash column chromatography to furnish 2-chloro-6-methyl-3-nitro-4-(3-pentyl)aminopyridine as a pale yellow solid (2.8 g; 84-85° C.). Elemental analysis for C₁₁ H₁₆ ClN₃ O₂ : Theory C: 51.27, H: 6.27, N: 16.30. Found: C: 51.28 , H: 6.09, N: 16.07.

Part C: The product of Part B from above was reduced in a manner similar to Part C of Example 1 to afford 3-amino-2-chloro-6-methyl-4-(3-pentyl)aminopyridine as a cream colored solid (mp 165-166° C.). Elemental analysis for C₁₁ H₁₈ ClN₃ : Theory C: 58.01, H: 7.98, N: 18.45. Found: C: 57.86, H: 7.83, N: 18.44.

Part D: The product of Part C from above was cyclized in a manner similar to Part E of Example 1 to afford 4-chloro-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine as a light pink solid (mp 78-79° C.).

Part E: The product of Part D from above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C in Example 21, to yield the title compound as a cream colored solid (mp 144-145° C.). Elemental analysis for C₂ OH26BrN5: Theory C: 57.69, H: 6.29, N: 16.82 Found: C: 57.82 , H: 6.29, N: 16.90.

EXAMPLE 222

N-(2-bromo-4,6-dimethoxyphenyl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c] pyridin-4-amine

The product of Part D from Example 221 was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a off-white solid (mp 166-167° C.). Elemental analysis for C₁₉ H₂₄ BrN₅ O₂ : Theory C: 52.54, H: 5.58, N: 16.12 Found: C: 52.63, H: 5.53, N: 16.16.

EXAMPLE 223

N-(2-chloro-4,6-dimethoxyphenyl)-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c] pyridin-4-amine

The product of Part D from Example 221 was combined with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as an off-white solid (mp 168-169° C.).

EXAMPLE 224

N-(2-bromo-4,6-dimethoxyphenyl)-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

Part A: The product of Part A from Example 221, was treated with 4-aminoheptane in the same manner as outlined in Part B of Example 221 to furnish 2-chloro-4-(4-heptyl)amino-6-methyl-3-nitropyridine as an yellow oil. Elemental analysis for C₁₃ H₂₀ C₁ N₃ O₂ : Theory C: 54.64, H: 7.05, N: 14.70. Found: C: 54.93, H: 7.03, N: 14.62.

Part B: The product of Part A from above was reduced in a manner similar to Part C of Example 1 to afford 3-amino-2-chloro-4-(4-heptyl)amino-6-methylpyridine as a cream colored solid (mp 139-140° C.).

Part C: The product of Part B from above was cyclized in a manner similar to Part E of Example 1 to afford 4-chloro-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c]pyridine as an orange yellow solid (mp 90-91° C.).

Part D: The product of Part C from above was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a brick red colored solid (mp 140-141° C.). Elemental analysis for C₂₁ H₂₈ BrN₅ O₂ : Theory C: 54.55, H: 6.10, N: 15.15 Found: C: 54.83, H: 5.95, N: 15.11.

EXAMPLE 225

N-(2-chloro-4,6-dimethoxyphenyl)-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-clpyridin-4-amine

The product of Part C from Example 224 was combined with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a brick red colored solid (mp 157-158° C.). Elemental analysis for C₂₁ H₂₈ ClN₅ O₂ : Theory C: 60.35, H: 6.75, N: 16.76 Found: C: 60.43, H: 6.74, N: 16.99.

EXAMPLE 226

(±)-N-[2-bromo-4-(1-methylethyl)phenyl]-1-(1-ethylpentyl)-6-methyl-1H-1,2,3-triazolo[4,5-c] pyridin-4-amine

Part A: The product of Part A from Example 221, was treated with 3-aminoheptane in the same manner as outlined in Part B of Example 221 to furnish 2-chloro-4-(3-heptyl)amino-6-methyl-3-nitropyridine as an yellow solid (mp 48-49° C.). Elemental analysis for C₁₃ H₂₀ ClN₃ O₂ : Theory C: 54.64, H: 7.05, N: 14.70. Found: C: 54.79, H: 6.95, N: 14.67.

Part B: The product of Part A from above was reduced in a manner similar to Part C of Example 1 to afford 3-amino-2-chloro-4-(3-heptyl)amino-6-methylpyridine as a cream colored solid (mp 139-140° C.)

Part C: The product of Part B from above was cyclized in a manner similar to Part E of Example 1 to afford 4-chloro-1-(1-ethylpropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine as a colored liquid. Elemental analysis for C₁₃ H₁₉ ClN₄ : Theory C: 58.53, H: 7.19, N: 21.00. Found: C: 58.69, H: 7.06, N: 20.76.

Part D: The product of Part C from above was combined with 2-bromo-4-isopropylaniline in a manner similar to Part C in Example 21, to yield the title compound as a light pink colored solid (mp 73-74° C.). Elemental analysis for C₂₂ H₃₀ BrN₅ : Theory C: 59.46, H: 6.80, N: 15.76, Found: C: 59.56, H: 6.70, N: 15.70.

EXAMPLE 227

(±)-N-(2-bromo-4,6-dimethoxyphenyl)-1-(1-ethylpentyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

The product of Part C from Example 226 was combined with 2-bromo-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a brick red colored solid (mp 127-128° C.). Elemental analysis for C₂₁ H₂₈ BrN₅ O₂ : Theory C: 54.55, H: 6.10, N: 15.15. Found: C: 54.78, H: 5.84, N: 14.92.

EXAMPLE 228

(±)-N-(2-chloro-4,6-dimethoxyphenyl)-1-(1-ethylpentyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

The product of Part C from Example 226 was combined with 2-chloro-4,6-dimethoxyaniline in a manner similar to Part C in Example 21, to yield the title compound as a brick red colored solid (mp 155-156° C.). Elemental analysis for C₂₁ H₂₈ ClN₅ O₂ : Theory C: 60.35, H: 6.75, N: 16.76. Found: C: 60.36, H: 6.65, N: 16.84.

EXAMPLE 229

N-[2-bromo-4-(1-methylethyl)phenyl]-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

Part A: 4-Chloro-6-methyl-3-nitropyridone: 4-Hydroxy-6-methyl-3-nitropyridone (4.0 g, 23,52 mmol) was treated with cyclohexylamine (2.8 mL, 24.46 mmol) in MeOH (50 mL) until all dissolved. The MeOH was stripped in vacuo and the resulting salt was dried and treated with POCl₃ (30 mL) at 25° C. for 30 h. The reaction was then poured into ice/water (400 mL) and extracted with EtOAc (2×200 mL). The combined EtOAc extracts were washed with water (100 mL), 1 N NaOH (20 mL), water (100 mL) and brine, dried (MgSO₄) and stripped in vacuo. The residue was washed with 20% EtOAc/hexanes (2×30 mL) to give the product (2.9 g).

Part B: 6-Methyl-3-nitro-4-(1-propylbutylamino) pyridone: 4-Chloro-6-methyl-3-nitropyridone (2.9 g, 15.40 mmol) was treated with 1-propylbutylamine (4 mL, 26.8 mmol) in CH₃ CN (30 mL) at 25° C. for 64 h and at reflux for 2 h. The reaction mixture was partitioned between EtOAc (200 mL) and water (50 mL). The EtOAc was washed with water (2×50 mL), brine, dried (MgSO₄) and stripped in vacuo. The residue was washed with 20% EtOAc/hexanes (2×20 mL) to give the product (3.7 g).

Part C: 2-Chloro-6-methyl-3-nitro-N-(1-propyl-butyl)pyridin-4-amine: 6-Methyl-3-nitro-4-(1-propylbutylamino) pyridone (3.7 g, 13.84 mmol), was treated with POCl₃ (14 mL) at 25° C. for 20 h. Then it was poured into ice/water (200 mL) and extracted with EtOAc (300 mL). The EtOAc was washed with water, brine, dried (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (3.3 g).

Part D: N-[2-Bromo-4-(1-methylethyl)phenyl]-6-methyl-3-nitro-N-(1-propylbutyl)pyridin-2,4-diamine: 2-Chloro-6-methyl-3-nitro-N-(1-propylbuty)pyridin-4-amine (0.5 g, 1.75 mmol) and 2-bromo-4-isopropylaniline (0.74 g, 3.5 mmol) were heated at 140° C. for 4.5 h. After cooling it was dissolved in CH₂ Cl₂ and filtered through a short column of silica gel. The filtrate was concentrated and chromatographed on silica gel (5% EtOAc/hexanes eluting solvent) to give the product (0.7 g).

Part E: N-[2-Bromo-4-(1-methylethyl)phenyl]-6-methyl-N-(1-propylbuty) pyridine-2,3,4-triamine: N-[2-Bromo-4-(1-methylethyl)phenyl]-6-methyl-3-nitro-N-(1-propyl-butyl)pyridin-2,4-diamine (0.7 g, 1.51 mmol), was suspended between dioxane (30 mL) and water (30 mL) containing conc.NH₄ OH (1.2 mL). To that Na₂ S₂ O₄ was added (2.1 g, 12.06 mmol) and the mixture was stirred at 25° C. for 2h. Then an additional 1 g Na₂ S₂ O₄ was added followd by 10 mL dioxane and 10 mL water. After stirring for 1 h at 25° C. the mixture was patritioned between EtOAc (120 mL) and water (20 mL). The EtOAc was washed with water (100 mL), brine, dried (MgSO₄) and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (0.5 g).

Part F: N-[2-bromo-4-(1-methylethyl)phenyl]-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine: N-[2-Bromo-4-(1-methylethyl)phenyl]-6-methyl-N-(1-propylbutyl) pyridine-2,3,4-triamine (0.5 g, 1.15 mmol), dissolved in CH₂ Cl₂ (6 mL) and 50% AcOH (4 mL) was treated with NaNO₂ (0.0846 g, 1.22 mmol) at 25° C. for 16 h. The mixture was patritioned between EtOAc (100 mL) and water (20 mL) The EtOAc was washed with water (20 mL), brine, dried and stripped in vacuo. The residue was chromatographed on silica gel (20% EtOAc/hexanes eluting solvent) to give the product (0.2 g). Anal. Calcd. for C₂₂ H₃₀ BrN₅ : C, 59.46; H, 6.80; N, 15.76; Br, 17.98. Found: C, 59.76; H, 6.83; N, 15.67; Br, 18.17.

EXAMPLE 231

N-[4-(1-methylethyl)-2-sulfonylmethylphenyl]-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c] pyridin-4-amine

N-[4-(1-methylethyl)-2-thiomethylphenyl]-6-methyl-1-(1-propylbutyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine (0.15 g, 1 equiv.) (Example 231), synthesized under the same general conditions of Example 229, was dissolved in methanol (3 mL) and water (2 mL) was added, followed by NaIO₄ (0.114 g, 1.5 equiv.). The mixture was stirred at 25° C. for 20 h and then was extracted with EtOAc (80 mL). The EtOAc was washed with water, brine, dried and stripped in vacuo. The residue was dissolved in CH₂ Cl₂ and a solution of KMnO₄ (0.15 g, 2.5 equiv.) in water (2 mL) was added, followed by benzyltriethylammonium chloride (0.15 g, 1.5 equiv.). The mixture was stirred at 25° C. for 20 h and then extracted with EtOAc (80 mL) and the EtOAc was washed with water, brine, dried and stripped in vecuo. The residue was chromatographed on silica gel (10% EtOAc/hexanes eluting solvent) to give the product (0.2 g). Anal. Calcd. for C₂₃ H₃₃ BrN₅ O₂ S: C, 62.27; H, 7.51; N, 15.79; S, 7.24. Found: C, 62.62; H, 7.38; N, 15.58 S, 7.44.

EXAMPLE 232

N-[4-(4-acetyl-2-bromophenyl]-6-methyl-1-(1-propyl-butyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

PART A: Used the standard procedure for the coupling of the nitropyridine (0.8 g, 2.9 mmoles) and 2-Bromo-4-iodoaniline (1.7 g, 5.7 mmoles). Preabsorbed the crude material on 12 g. of silica gel before chromatographing on silica gel (5% EtOAc/hexane eluen) to give an orange solid, 1.47 g. of the desired product.

PART B: To the coupled 2-Bromo-4-iodoanilinonitropyridine (0.60 g, 1.1 mmoles) in a dried flask, under nitrogen, was added Bis(triphenylphosphine)palladium(II)chloride (18 mg, 0.026 mmoles) and anhydrous toluene (5 mL). Added 1-Ethoxyvinyltributyltin (0.46 ml, 1.36 mmoles) and stirred at reflux temperature for 11/2 hours. Dissolved into ethyl acetate then filtered off the insolubles through celite. Washed the solids 2× with ethyl acetate. Concentrated in-vacuo the filtrates to near dryness. Stirred the residue with 70 ml 1M hydrochloric acid for 1/2 hour. Added some ethyl acetate and separated the layers, extracted the water layer with 2×20 ml ethyl acetate. Concentrated the combined organics to near dryness. Stirred the residue in a saturated potassium fluoride (20 ml) for 1/2 hour. Separated the layers. Extracted the water layer with 2×20 ml ethyl acetate. Washed the combined extracts with 10 ml water and 20 ml brine. Chromatographed the crude material on silica gel to give a solid, 0.37 g (73 %) of the desired product.

PART C: Using the product obtained from Part B (0.70 g, 1.5 mmoles), 10 ml tetrahydrofuran, 10 ml water, 0.70 ml ammonium hydroxide solution (38-40%) and sodium dithionite (2.1 g, 12 mmoles) followed the standard procedure to reduce the nitroanilinopyridine. Obtained the crude solid, 0.65 g, which was of sufficient purity for further reaction.

PART D: Followed the standard procedure to cyclize the product obtained in Part C (0.63 g, 1.45 mmoles), using 10 ml methylene chloride, 10 ml acetic acid/water (50%), and sodium nitrite (0.18 g, 2.59 mmoles) in 1 ml water. Chromatographed on silica gel (10% ethyl acetate/hexane) to give a white solid, 0.31 g, (48%) of desired product, mp 165-166° C. Anal. Calcd. for C₂₁ H₂₆ BrN₅ O: C, 56.76; H, 5.91; N, 15.76; Br, 17.98. Found: C, 56.75; H, 5.76; N, 15.71; Br, 17.72. Obtained the isomer of the desired product, a white solid, 90 mg, mp 133-136° C. Anal. Calcd: Found: C, 57.11; H, 5.82; N, 15.69; Br, 18.23.

The rest of the examples shown in Table 4 were prepared by following the general procedure outlined in Example 229.

                  TABLE 4                                                          ______________________________________                                         1H-1,2,3-triazolo[4,5-c]pyridines:                                              ##STR32##                                                                     Ex.                                Mp                                          No.   R.sup.3       Ar             ° C.                                 ______________________________________                                         233   CH(Et)CH.sub.2 --OCH.sub.3                                                                   2-Br-4-i-Pr-Ph 121-123                                     234   CH(Et)CH.sub.2 --OCH.sub.3                                                                   4-i-Pr-2-SMe-Ph                                                                                97-100                                     235   CH(i-C.sub.3 H.sub.7).sub.2                                                                  2-Br-4-(iC.sub.3 H.sub.7)Ph                                                                    96-96                                      236   CH(i-C.sub.3 H.sub.7).sub.2                                                                  4-(i-C.sub.3 H.sub.7)-2-SMe-Ph                             237   CH(C.sub.2 H.sub.5).sub.2                                                                    4-(i-C.sub.3 H.sub.7)-2-SMe-Ph                             238   CH(n-C.sub.3 H.sub.7).sub.2                                                                  2-Br-4-I-Ph    161-164                                     239   CH(n-C.sub.3 H.sub.7).sub.2                                                                  2,4-(Br).sub.2 -Ph                                                                            125-127                                     240   CH(Et)CH.sub.2 --OCH.sub.3                                                                   2,4,6-Me.sub.3 -Ph                                         241   i-Pr          2-Br-4-i-Pr-Ph                                             242   i-Pr          4-i-Pr-2-SMe-Ph                                            243   c-Pr          2-Br-4-i-Pr-Ph                                             244   c-Pr          4-i-Pr-2-SMe-Ph                                            245   i-Pr          2,4-(Br).sub.2 -Ph                                         246   c-Pr          2,4-(Br).sub.2 -Ph                                         247   CH(Et)CH.sub.2 --OCH.sub.3                                                                   2,4-(Br).sub.2 -Ph                                         248   CH(Et).sub.2  2,4-(Br).sub.2 -Ph                                         249   CH(Et)CH.sub.2 --OCH.sub.3                                                                   2-COMe-4-Br-Ph                                             250   CH(Et).sub.2  4-COMe-2-Br-Ph                                             251   CH(Et).sub.2  2-Br-4-SO.sub.2 Me-Ph                                      252   CH(Et).sub.2  2,4,6-Me.sub.3 -Ph                                         253   CH(CH.sub.2 CN).sub.2                                                                        2-Br-4-(i-C.sub.3 H.sub.7)Ph                               254   CH(Et)CH.sub.2 CN                                                                            2-Br-4-(i-C.sub.3 H.sub.7)Ph                               255   CH(Et)CH.sub.2 CONMe.sub.2                                                                   2-Br-4-(i-C.sub.3 H.sub.7)Ph                               256   CH(CH.sub.2 CN).sub.2                                                                        2-Br-4,6-(OMe).sub.2 Ph                                    257   CH(Et)CH.sub.2 CN                                                                            2-Br-4,6-(OMe).sub.2 Ph                                    258   CH(Et)CH.sub.2 CONMe.sub.2                                                                   2-Br-4,6-(OMe).sub.2 Ph                                    ______________________________________                                    

EXAMPLE 259

N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine:

Part A: Serinol (24 g) was added to a solution of trityl chloride (65 g) and triethylamine (51.0 g) in 600 mL of dry DMF. After stirring at room temperature for 48 h, the reaction was poured into water and extracted several times with diethyl ether. The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to dryness to afford N-triphenylmethylserinol (71.0 g).

Part B: Methyl iodide (90 mL) was added to a suspension of N-triphenylmethylserinol (37.0 g) and powdered sodium hydroxide (45.0 g) in 400 mL of dry DMSO. After stirring at room temperature for 24-36 h, the reaction was added to water (800 mL) and extracted with diethyl ether (3×500 mL). The combined organic layers was washed with water (4×250 mL), dried over anhydrous magnesium sulfate and concentrated to afford 1,3-dimethoxy-2-triphenylmethylaminopropane (36.0 g) as a thick viscous oil.

Part C: To a solution of the product of Part B (36.0 g) in methanol (400 mL) was added 1 M HCl in ether (350 mL). After stirring overnight, the reaction was poured over water (800 mL) extracted with hexane (3×250 mL). The methanol/water layer was concentrated to dryness to afford 1,3-dimethoxy-2-aminopropane hydrochloride (14.0 g) as a waxy solid.

Part D: 4-Chloro-6-methyl-3-nitro-2-pyridone: 4-Hydroxy-6-methyl-3-nitro-2-pyridone (50.0 g) was treated with cyclohexylamine (40 g) in MeOH (300 mL) and heated until all dissolved. The MeOH was stripped in vacuum and the resulting salt was dried and treated with POCl₃ (360 mL) at 25° C. for 48 h. The excess POCl₃ was removed under vacuum and the residue was poured into ice/water (1000 mL) and extracted with EtOAc (4×250 mL). The combined EtOAc extracts were washed with aq. NaHCO₃, brine (3 *100 mL), dried (MgSO₄) and stripped in vacuum. The residue was washed with 20% EtOAc/hexanes (2×100 mL) to afford the product as a yellow solid(41.3 g; mp 225° C.).

Part E: 4-[l-methoxymethyl-(2-methoxyethyl]amino-6-methyl-3-nitro-2-pyridone: 4-Chloro-6-methyl-3-nitro-2-pyridone (12.12 g; from part D) was treated with 1,3-dimethoxy-2-aminopropane hydrochloride (10.0 g; from part C) in CH₃ CN (200 mL) and diisopropylethylamine (20.0 g) at 25° C. for 24 h and at reflux for 3 h. The reaction mixture was partitioned between EtOAc (200 mL) and water (50 mL). The EtOAc was washed with water (2×50 mL), brine, dried (MgSO₄) and stripped in vacuum to give the product as a yellow solid (9.4 g; m.p.172-173° C.).

Part F: 2-Chloro-N-1-methoxymethyl-(2-methoxyethyl]-6-methyl-3-nitro-pyridin-4-amine: 4-[1-methoxymethyl-(2-methoxyethyl]amino-6-methyl-3-nitro-2-pyridone (9.4 g from part E), was treated with POCl₃ (55 mL) at 25° C. for 24 h. The excess POCl₃ was removed under vacuum, and the residue was poured into ice/water (200 mL) and extracted with CH₂ Cl₂ (3×150 ML). The combined CH₂ Cl₂ extract was washed with water, dried (MgSO₄) and stripped in vacuum to give the product as a yellow solid (9.0 g; m.p. 85-87° C.).

Part G: 2-Chloro-4-[1-methoxymethyl-(2-methoxyethyl]amino-6-methylpyridin-3-amine: The product of Part F (9.0 g) was added to acetic acid (80 mL) and methanol (400 mL). To this mixture was added iron powder (9.0 g) in portions, stirred for 5 h at 60-65° C., cooled to room temperature, and filtered through celite. The filtrate was stripped to a brown solid, which was extracted with ethyl acetate (2×150 mL), washed with NaHCO₃ (100 mL), and brine (100 mL). The organic layer was dried over anhydrous magnesium sulfate, filtered and stripped down to yield the product as a pale yellow solid (5.6 g; m.p. 100° C.).

Part H: 4-Chloro-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine: The product of Part G (5.4 g) was dissolved in dichloromethane (100 mL) and 50 % aqueous acetic acid (100 mL). To this stirred mixture was added sodium nitrite (1.7 g) in water (10 mL) dropwise at room temperature. After completion of addition, the reaction was stirred for an additional 15 mins. The organic layer was separated, washed with water, dried with anhydrous magnesium sulfate, and stripped down to a residue. The residue was purified by flash column chromatography (CH₂ Cl₂) to afford the product as a pale yellow solid (5.4 g; m.p. 49-50° C.).

Part I: N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine: The product of Part H (2.0 g) from above was combined with 2-chloro-4,6-dimethylaniline (1.4 g) in the presence of p-toluenesulfonic acid (1.7 g) in toluene (25.0 mL) at 110° C. for 4h. The reaction mixture was partitioned between EtOAC (50 mL) and aq. NaHCO₃ (50 mL), washed the organic layer with brine, dried and stripped in vacuum to a residue. The residue was purified by flash column chromatography (1:100::MeOH: CH₂ Cl₂) to afford the title compound as white solid (1.7 g; mp 83-84° C.) after crystallization from ether/pentane. Elemental analysis for C₁₉ H₂₄ ClN₅ O₂ : Theory C: 58.53, H: 6.20, N: 17.96, Cl: 9.09. Found: C: 58.69, H: 6.32, N: 17.97, Cl:9.18.

Part J: Mesylate salt of N-(2-chloro-4,6-dimethylphenyl)-1-[1-methoxymethyl-(2-methoxyethyl]-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine: The product of Part I (850 mg) was dissolved in dichloromethane (5.0 mL) and then added methanesulfonic acid (250 mg). The solvent was removed and the residue was crystallized from 2-propanol (2.5 mL) to afford the mesylate salt (920 mg; m.p. 179-180° C.) as a white crystalline solid. Elemental analysis for C₂₀ H₂₈ ClN₅ O₅ S: Theory C: 49.43, H: 5.82, N: 14.41. Found: C: 49.42, H: 5.79, N: 14.37.

The compounds listed in Tables 5 and 6 were prepared by the methods exemplified in Examples 1-53 and 526.

                  TABLE 5                                                          ______________________________________                                         3H-1,2,3-triazolo[4,5-d]pyrimidines:                                            ##STR33##                                                                     Ex. No.                                                                              Ar             R.sup.3       m.p. (° C.)                          ______________________________________                                         260   2-Br-2,6-(Me).sub.2 -Ph                                                                       CH(Et).sub.2  134-135                                     261   2-Cl-2,6-(Me).sub.2 -Ph                                                                       CH(Et).sub.2  133-134                                     262   4-Br-2-Cl-6-Me-Ph                                                                             CH(Et).sub.2  132-133                                     263   2,4-(Cl).sub.2 -6-Me-Ph                                                                       CH(Et).sub.2  132-133                                     264   2,4-(Br).sub.2 -6-F-Ph                                                                        CH(Et).sub.2  186-188                                     265   4-Br-2-Me-Ph   CH(Et).sub.2   125-127                                    266   4-NMe.sub.2 -2-Me-Ph                                                                          CH(Et).sub.2  136-137                                     267   4-Cl-2-Me-Ph   CH(Et).sub.2   116-118                                    268   4-I-2-Me-Ph    CH(Et).sub.2  139-140                                     269   4-NMe.sub.2 -2,6-(Me).sub.2 -Ph                                                               CH(Et).sub.2   160-161                                    270   2-Cl-4-Me-Ph   CH(Et).sub.2   100-101                                    271   2-Br-4-OMe-Ph  CH(Et).sub.2   146-147                                    272   2-Br-4-NMe.sub.2 -Ph                                                                          CH(Et).sub.2   166-167                                    273   2-Me-4-CH.sub.2 OMe-Ph                                                                        CH(Et).sub.2  oil                                         274   2-CN-4-Me-Ph   CH(Et).sub.2   221-223                                    275   4-CN-2-Me-Ph   CH(Et).sub.2   216-218                                    276   2,4,6-Me.sub.3 -Ph                                                                            CH(nPr)Me      140.5-142                                  277   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(nPr)Me      131-133                                    278   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(nPr)Me     amorph.                                     279   2-Cl-4,6-(OMe).sub.2 -Ph                                                                      CH(nPr)Me      144-145                                    280   2,4,5-Me.sub.3 -Ph                                                                            CH(nPr)Me      110-112                                    281   4-Cl-2-Me-Ph   CH(nPr)Me       99-101                                    282   4-Br-2-Me-Ph   CH(nPr)Me       83-84.5                                   283   4-I-2-Me-Ph    CH(nPr)Me      104-105                                    284   2,4-Me.sub.2 -Ph                                                                              CH(nPr)Me       74.5-76.5                                 285   2-Br-4-CH(Me).sub.2 -Ph                                                                       CH(nPr)Me     amorph.                                     286   2-Br-4-Cl-Ph   CH(nPr)Me      104-108                                    287   2-Br-4-NMe.sub.2 -Ph                                                                          CH(nPr)Me     Amorph.                                     288   4-NMe.sub.2 -2-Me-Ph                                                                          CH(nPr)Me     amorph.                                     289   2,4-(Me).sub.2 -Ph                                                                            CH(Et)n-Pr      88-89                                     290   4-OMe-2-Me-Ph  CH(Et)n-Pr     111-112                                    291   2,4-(SMe).sub.2 -Ph                                                                           CH(Et)n-Pr      65-66                                     292   2-Br-4-CF.sub.3 -Ph                                                                           CH(Et)n-Pr      91-92                                     293   4-Ac-2-Br-Ph   CH(Et)n-Pr     138-139                                    294   4-NMe.sub.2 -2-Me-Ph                                                                          CH(Et)n-Pr     116.5-118                                  295   4-Cl-2-Me-Ph   CH(Et)n-Pr    amorph.                                     296   4-I-2-Me-Ph    CH(Et)n-Pr    110-111.5                                   297   2,6-Me.sub.2 -4-I-Ph                                                                          CH(Et)n-Pr     158-160                                    298   4-Ac-2-Me-Ph   CH(Et)n-Pr     107-110.5                                  299   2-NMe.sub.2 -4-Me-Ph                                                                          CH(Et)n-Pr     106-107                                    300   4-NMe.sub.2 -2,6-(Me).sub.2 -Ph                                                               CH(Et)n-Pr     146-148                                    301   2,4-(SMe).sub.2 -Ph                                                                           CH(n-Pr).sub.2                                                                                105-106                                    302   4-OMe-2-Me-Ph  CH(n-Pr).sub.2                                                                                109-110                                    303   2-Br-4-N(Me).sub.2 -Ph                                                                        CH(n-Pr).sub.2                                                                                102-103                                    304   2,4-(Me).sub.2 -Ph                                                                            CH(n-Pr).sub.2                                                                                 97-98                                     305   4-Ac-2,6-(Me).sub.2 -Ph                                                                       CH(n-Pr).sub.2                                                                                162-164                                    306   4-Cl-2-Me-Ph   CH(n-Pr).sub.2                                                                                126-127.5                                  307   4-NMe.sub.2 -2-Me-Ph                                                                          CH(n-Pr).sub.2                                                                                129-130.5                                  308   4-I-2-Me-Ph    CH(n-Pr).sub.2                                                                                98.5-101                                   309   2-Me-4-CH.sub.2 OMe-Ph                                                                        CH(n-Pr).sub.2                                                                               oil                                         310   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(Et)CH.sub.2 OMe                                                                            140-141                                    311   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(Et)CH.sub.2 OMe                                                                            139-140                                    312   2-Cl-4,6-(Me).sub.2 -Ph                                                                       CH(Et)CH.sub.2 OMe                                                                            141-142                                    313   4-Br-2-Cl-6-Me-Ph                                                                             CH(Et)CH.sub.2 OMe                                                                            121-122                                    314   2,4-(Cl).sub.2 -6-Me-Ph                                                                       CH(Et)CH.sub.2 OMe                                                                            109-110                                    315   2,4-(Br).sub.2 -6-F-Ph                                                                        CH(Et)CH.sub.2 OMe                                                                           147-148                                     316   2-Br-3,4,6-(Me).sub.3 -Ph                                                                     CH(Et)CH.sub.2 OMe                                                                            166-167                                    317   3-Br-2,4,6-(Me).sub.3 -Ph                                                                     CH(Et)CH.sub.2 OMe                                                                            147-148                                    318   4-Br-2,6-(F).sub.2 -Ph                                                                        CH(Et)CH.sub.2 OMe                                                                            148-149                                    319   2-Br-4-Cl-6-F-Ph                                                                              CH(Et)CH.sub.2 OMe                                                                           139-140                                     320   2-Br-4,6-(F).sub.2 -Ph                                                                        CH(Et)CH.sub.2 OMe                                                                           124-125                                     321   4-CN-2,6-(Cl).sub.2 -Ph                                                                       CH(Et)CH.sub.2 OMe                                                                            180-181                                    322   2,4-(SMe).sub.2 -Ph                                                                           CH(Et)CH.sub.2 OMe                                                                             75-77                                     323   2-Br-4-N(Me).sub.2 -Ph                                                                        CH(Et)CH.sub.2 OMe                                                                            110-112                                    324   2-Cl-4-CN-6-Me-Ph                                                                             CH(Et)CH.sub.2 OMe                                                                            145-146                                    325   2-Cl-4-CN-Ph   CH(Et)CH.sub.2 OMe                                                                            140                                        326   2,4,5-(Me).sub.3 -Ph                                                                          CH(Et)CH.sub.2 OMe                                                                           108-109                                     327   2,4-(Me).sub.2 -Ph                                                                            CH(Et)CH.sub.2 OMe                                                                            104-105                                    328   4-Br-2,6-(Et).sub.2 -Ph                                                                       CH(Et)CH.sub.2 OMe                                                                            151-152                                    329   4-Br-2,6-(Cl).sub.2 -Ph                                                                       CH(Et)CH.sub.2 OMe                                                                           109-110                                     330   2-Br-4,6-(Cl).sub.2 -Ph                                                                       CH(Et)CH.sub.2 OMe                                                                           113-114                                     331   2,6-(Br).sub.2 -4-Cl-Ph                                                                       CH(Et)CH.sub.2 OMe                                                                           153-154                                     332   4-Br-2-Me-6-NO.sub.2 -Ph                                                                      CH(Et)CH.sub.2 OMe                                                                            150-151                                    333   4-OMe-2-Me-Ph  CH(Et)CH.sub.2 OMe                                                                           128-129                                     334   2,5-Cl.sub.2 -4-NMe.sub.2 -Ph                                                                 CH(Et)CH.sub.2 OMe                                                                             84-85                                     335   2,4-Cl.sub.2 -Ph                                                                              CH(Et)CH.sub.2 OMe                                                                            114-116                                    336   2-Br-4-Cl-Ph   CH(Et)CH.sub.2 OMe                                                                           133.5-135                                   337   4-Cl-2-Me-Ph   CH(Et)CH.sub.2 OMe                                                                           amorph.                                     338   4-I-2,6-Me.sub.2 -Ph                                                                          CH(Et)CH.sub.2 OMe                                                                           148.5-150                                   339   4-NMe.sub.2 -2,6-(Me).sub.2 -Ph                                                               CH(Et)CH.sub.2 OMe                                                                           144-146                                     340   2-Cl-4-Me-Ph   CH(Et)CH.sub.2 OMe                                                                             88-89                                     341   2-Br-4-OMe-Ph  CH(Et)CH.sub.2 OMe                                                                            118-120                                    342   2-Me-4-CH.sub.2 OMe-Ph                                                                        CH(Et)CH.sub.2 OMe                                                                           oil                                         343   2,4,6-Me.sub.3 -Ph                                                                            CH(Et)CH.sub.2 OEt                                                                            127-130                                    344   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(Et)CH.sub.2 OEt                                                                             61-62                                     345   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(Et)CH.sub.2 OEt                                                                            104-107                                    346   2,4-Me.sub.2 -Ph                                                                              CH(Et)CH.sub.2 OEt                                                                           oil                                         347   2-Br-4-Me-Ph   CH(Et)CH.sub.2 OEt                                                                            100-102                                    348   2,4,6-Me.sub.3 -Ph                                                                            CH(Et)CH.sub.2 OEt                                                                             94-96.5                                   349   2,4,6-Me.sub.3 -Ph                                                                            CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                               136-138                                    350   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                              amorph.                                     351   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                               139-140.5                                  352   2,4-Me.sub.2 -Ph                                                                              CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                              oil                                         353   2-Br-4-Me-Ph   CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                              100.5-102                                   354   2,4,5-Me.sub.3 -Ph                                                                            CH(C.sub.3 H.sub.7)CH.sub.2 OMe                                                               122-124                                    355   2,4,6-Me.sub.3 -Ph                                                                            CH(CHMe.sub.2)CH.sub.2 OMe                                                                    94-96.5                                    356   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(CHMe.sub.2)CH.sub.2 OMe                                                                    155-156                                    357   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(CHMe.sub.2)CH.sub.2 OMe                                                                   156-159                                     358   2,4-Me.sub.2 -Ph                                                                              CH(CHMe.sub.2)CH.sub.2 OMe                                                                    99-103                                     359   2-Br-4-Me-Ph   CH(CHMe.sub.2)CH.sub.2 OMe                                                                    93-95                                      360   2,4,5-Me.sub.3 -Ph                                                                            CH(CHMe.sub.2)CH.sub.2 OMe                                                                   130-131                                     361   2,4,6-Me.sub.3 -Ph                                                                            CH(sec-Bu)CH.sub.2 OMe                                                                        168-170.5                                  362   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(sec-Bu)CH.sub.2 OMe                                                                       136-139                                     363   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(sec-Bu)CH.sub.2 OMe                                                                        139-142                                    364   2,4-Me.sub.2 -Ph                                                                              CH(sec-Bu)CH.sub.2 OMe                                                                         85-87                                     365   2-Br-4-Me-Ph   CH(sec-Bu)CH.sub.2 OMe                                                                         78.5-80                                   366   2,4,5-Me.sub.3 -Ph                                                                            CH(sec-Bu)CH.sub.2 OMe                                                                        150-153                                    367   2,4,6-Me.sub.3 -Ph                                                                            CH(isoBu)CH.sub.2 OMe                                                                        126.6-129                                   368   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(isoBu)CH.sub.2 OMe                                                                         103-10                                     369   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(isoBu)CH.sub.2 OMe                                                                        127.5-130                                   370   2,4-Me.sub.2 -Ph                                                                              CH(isoBu)CH.sub.2 OMe                                                                        amorph.                                     371   2-Br-4-Me-Ph   CH(isoBu)CH.sub.2 OMe                                                                          99-100.5                                  372   2,4,5-Me.sub.3 -Ph                                                                            CH(isoBu)CH.sub.2 OMe                                                                        134-138                                     373   2-Cl-4,6-Me.sub.2 -Ph                                                                         CH(CH.sub.2 OMe).sub.2                                                                        98-99                                      374   4-Br-2,6-Me.sub.2 -Ph                                                                         CH(CH.sub.2 OMe).sub.2                                                                       115-116                                     375   4-OMe-2-Ph-Ph  CH(CH.sub.2 OMe).sub.2                                                                        55-57                                      376   3-Br-2,4,6-Me.sub.3 -Ph                                                                       CH(CH.sub.2 OMe).sub.2                                                                       151-152                                     377   4-Br-2,6-Et.sub.2 -Ph                                                                         CH(CH.sub.2 OMe).sub.2                                                                        154-155                                    378   2,4,6-(Me).sub.3 -Ph                                                                          CH(CH.sub.2 OMe).sub.2                                                                        136-137                                    379   4-Br-2-Me-Ph   CH(CH.sub.2 OMe).sub.2                                                                        104-108                                    380   2-Br-4-Cl-Ph   CH(CH.sub.2 OMe).sub.2                                                                       123-125                                     381   2,4-Cl.sub.2 -Ph                                                                              CH(CH.sub.2 OMe).sub.2                                                                        87.5-90                                    382   4-NMe.sub.2 -2-Me-Ph                                                                          CH(CH.sub.2 OMe).sub.2                                                                       159-162                                     383   4-Cl-2-Me-Ph   CH(CH.sub.2 OMe).sub.2                                                                       100-102                                     384   4-I-2-Me-Ph    CH(CH.sub.2 OMe).sub.2                                                                       116-117.5                                   385   2,6-Me.sub.2 -4-I-Ph                                                                          CH(CH.sub.2 OMe).sub.2                                                                       amorph.                                     386   2-NMe.sub.2 -4-Me-Ph                                                                          CH(CH.sub.2 OMe).sub.2                                                                        100-102                                    387   2-Br-4-Me-Ph   CH(CH.sub.2 OMe).sub.2                                                                        106-108                                    388   2-Cl-4-Me-Ph   CH(CH.sub.2 OMe).sub.2                                                                       114-115                                     389   4-NMe.sub.2 -2,6-(Me).sub.2 -Ph                                                               CH(CH.sub.2 OMe).sub.2                                                                         71-73                                     390   2-Br-4-OMe-Ph  CH(CH.sub.2 OMe).sub.2                                                                        127-128                                    391   2-Br-4-NMe.sub.2 -Ph                                                                          CH(CH.sub.2 OMe).sub.2                                                                        139-141                                    392   2-Me-4-CH.sub.2 OMe-Ph                                                                        CH(CH.sub.2 OMe).sub.2                                                                       oil                                         393   2,4,6-Me.sub.3 -Ph                                                                            CH(Et)CH.sub.2 Ph                                                                            amorph.                                     394   2,4,6-Me.sub.3 -Ph                                                                            2-OMe-6-Me-Ph  202-205                                    395   2,4,6-Me.sub.3 -Ph                                                                            CH(Et)CH.sub.2 OH                                                                            amorph.                                     396   2,4,6-Me.sub.3 -Ph                                                                            CH(Me)isoBu    126-127                                    397   2,4,6-Me.sub.3 -Ph                                                                            CH(Me)isoPr   161-162                                     398   2,4,6-Me.sub.3 -Ph                                                                            cyclopentyl    174-175                                    399   2,4,6-Me.sub.3 -Ph                                                                            cyclohexyl    198-199                                     400   2,4,6-Me.sub.3 -Ph                                                                            4-methylcyclohexyl                                                                           178-180                                     ______________________________________                                          Note: (+), (-), (R) or (S) denotes respective isomers                    

                  TABLE 6                                                          ______________________________________                                         3H-1,2,3-triazolo[4,5-d]pyrimidines:                                            ##STR34##                                                                     Ex. No.  Ar            R.sup.1   m.p. (° C.)                            ______________________________________                                         401      2,4,6-Me.sub.3 -Ph                                                                           H         146-147                                       402      4-Br-2,6-Me.sub.2 -Ph                                                                        H         139-140                                       403      2,4,6-Me.sub.3 -Ph                                                                           CF.sub.3  176-177                                       404      4-Br-2,6-Me.sub.2 -Ph                                                                        CF.sub.3  183-184                                       405      2-Cl-4,6-Me.sub.2 -Ph                                                                        CF.sub.3  174-175                                       406      2,4-Cl.sub.2 -6-Me-Ph                                                                        CF.sub.3  160-161                                       407      2-Cl-4,6-Me.sub.2 -Ph                                                                        C.sub.2 H.sub.5                                                                          111-112                                       408      2-Cl-4,6-Me.sub.2 -Ph                                                                        MeOCH.sub.2                                                                               87-88                                        ______________________________________                                    

EXAMPLE 409

6-[N-(2-chloro-4,6-dimethylphenyl)]-9-[(1-methoxymethyl)propyl]-2-methyl-9H-purin-6,8-diamine:

Part A: 2-methyl-4-chloro-6-(1-methoxymethyl) propylamino-5-aminopyridine (450 mg, 1.84 mmol) was reacted with cyanogen bromide (234 mg, 2.2 mmol) in refluxing methanol for 24 h. The solvent was removed in vacuo and the resulting crude oil was taken up in ethyl acetate and washed 3 times with saturated aqueous NaHCO₃. The organic layer was dried then stripped in vacuo and the crude product was chromatographed on silica gel (20 g, ethyl acetate neat) providing 240 mg (48%) of 8-amino-6-chloro-9-[(1-methoxymethyl)propyl-2-methyl-9H-purine.

Part B: The product from part B (50 mg, 0.20 mmol) was treated with 2-chloro-4,6-dimethylaniline (30 mg, 0.20 mmol) in refluxing 1.0 N HCl for 24 h. The reaction was cooled then poured into saturated aqueous NaHCO₃ and extracted (3 times 50 ml) with ethyl acetate. The organic fractions were combine, dried and stripped in vacuo. The resulting crude product was chromatographed on silica gel (20 g, ethyl acetate neat) providing 55 mg (71%) of the title compound. Anal. Calcd. for C₁₉ H₂₅ N₆ OCl: C, 58.76; H, 6.44; N, 21.65. Found: C, 58.50; H, 6.32; N, 21.72.

The compounds of Table 7 can be made by the methods exemplified in Examples 209-211 and 409.

                  TABLE 7                                                          ______________________________________                                         9H-imidazo[4,5-d]pyrimidines:                                                   ##STR35##                                                                     Ex.                                                                            No.  Ar            R.sup.2                                                                               R.sup.3    m.p. (° C.)                        ______________________________________                                         410  2,4,6-(Me).sub.3 -Ph                                                                         H      CH(Et)CH.sub.2 OCH.sub.3                                                                  212-213                                   411  2,4,6-(Me).sub.3 -Ph                                                                         NH.sub.2                                                                              CH(Et)CH.sub.2 OCH.sub.3                                                                  oil                                       412  2-Cl-4,6-(Me).sub.2 -Ph                                                                      NH.sub.2                                                                              CH(CH.sub.2 OCH.sub.3).sub.2                                                              oil                                       413  2,4,6-(Me).sub.3 -Ph                                                                         NH.sub.2                                                                              CH(CH.sub.2 OCH.sub.3).sub.2                                                              oil                                       ______________________________________                                    

EXAMPLE 414

(S)-(-)-N-(2-chloro-4,6-dimethylphenyl]-6-methyl-1-(1-methoxymethyl-3-methoxypropyl)-1H-1,2,3-triazolo[4,5-c]pyridin-4-amine

Part A: L-Dimethyl aspartate hydrochloride (5 g, 25.3 mmol) and triphenylmethyl chloride (7.65 g, 27.5 mmol) were suspended in dry CH₃ CN (50 mL) at 0° C. To that Et₃ N (4.5 mL, 32.3 mmol) was added dropwise, followed by N-methylmorpholine (2.5 mL, 27.5 mmol). The mixture was stirred at 0° C. for 1 h and at 25° C. for 30 min. Then it was partitioned between EtOAc (200 mL) and water (50 mL) and the organic extract was washed with water (50 mL), brine (50 mL), dried (MgSO₄) and stripped in vacuo. The product, diethyl N-triphenylmethyl aspartate, was >90% clean by NMR analysis. NMR(CDCl₃)d 7.16-7.51 (m, 15 H), 3.68 (s, 3H), 3.66-3.74 (m, 1H), 3.26 (s, 3H), 2.93 (d, 1H, J=9.9Hz), 2.63-2.69 (dd, 1H, J₁ =14.6, J₂ =5.1 Hz), 2.48-2.55 (dd, 1H, J₁ =14.6 Hz, J₂ =7 Hz).

Part B: (S)-Diethyl N-triphenylmethyl aspartate (˜25 mmol) was dissolved in dry THF (150 mL) and cooled to 0° C. To that a 1 M solution of of LiAlH₄ in THF (50 mL, 50 mmol) was added dropwise and the reaction was stirred for 2 h and allowed to warm to 25° C. Then it was cooled and quenched with water (5 mL) and 1 N NaOH (4 mL), diluted with ether (200 mL) and the precipitated solids were filtered off. The filtrate was concentrated in vacuo to give the product, 2-N-triphenylainino-1,4-butane diol (>90% clean by NMR analysis). NMR(CDCl₃)d 7.17-7.57 (m, 15H), 3.68-3.77 (m, 1H), 3.56-3.63 (m, 1H), 3.19 (d, 1H, J=8.8 Hz), 2.76-2.86 (m, 2H), 2.2-2.7 (br, 3H), 1.54-1.63 (m, 1H), 1.36-1.54 (m, 1H).

Part C: (S)-2-N-triphenylamino-1,4-butane diol (˜25 mmol) dissolved in dry THF (50 mL) was added into a suspension of NaH 60% in oil (2.34 g, 58.5 mmol) in dry THF (50 mL) at 0° C., and the mixture was stirred at 9° C. for 30 min and at 25° C. for 1 h. Then it was cooled in an ice bath and CH₃ I (3.6 inL, 58.5 mmol) was added dropwise. The reaction was stirred at 0° C. for 30 min and at 25° C. for 2 h, the excess NaH was quenched with water and the THF was stripped off. The residue was partitioned between EtOAc (200 mL) and water (50 mL) and the organic extract was washed with water (50 mL), brine (50 mL), dried (MgSO₄) and stripped in vacuo. The product, 2-N-triphenylamino-1,4-dimethoxy butane was >90% clean by NMR analysis. NMR(CDCl₃)d 7.15-7.59 (m, 15 H), 3.34-3.41 (m, 1H), 3.22-3.30 (in, lH), 3.24 (s, 3H), 3.03 (s, 3H), 2.86 (dd, 1H, J₁ =9.5 Hz, J₂ =3.3 Hz), 2.65-2.75 (m, 1H), 2.4-2.46 (br, 1H), 2.30-2.35 (m, 1H), 2.57-2.8 (m, 2H).

Part D: (S) -2-N-Triphenylamino-1,4-dimethoxy butane (˜25 mmol) was dissolved in a mixture of CH₂ Cl₂ (100 mL) and methanol (50 mL) and 1 M HCl in ether was added (50 mL). The reaction was stirred at 25° C. for 16 h, the solvent was stripped off and the residue was washed with 1:1 ether/hexane (3×50 mL). The remaining oil, 2-amino-1,4-dimethoxybutane hydrochloride, was dried under vacuum (3.87 g, 88%). NMR(CDCl₃)d 8.2-8.5 (br, 3H), 3.5-3.7 (m, 5H), 3.41 (s, 3H), 3.36 (s, 3H), 2.05-2.2 (m, 1H), 1.90-2.01 (m, 1H).

Part E: (S)-6-Methyl-3-nitro-4-(1-methoxymethyl-3-methoxypropylamino) pyridone: 1-methoxymethyl-3-methoxypropylamine (4.19 g, 22.3 mmol), and 4-chloro-6-methyl-3-nitropyridone (3.87 g, 22.3 mmol) were mixed in CH₃ CN (70 mL) and diisopropyl-ethylamine (9.4 mL, 53.6 mmol) was added. The reaction was stirred at 25° C. for 16 h and at reflux for 2.5 h. The solvent was stripped off and the residue was dissolved in CH₂ Cl₂ (150 mL) and the CH₂ Cl₂ was washed with water (80 mL). The water was extracted with CH₂ Cl₂ (50 mL) and the combined organic extracts were dried (MgSO₄) and stripped in vacuo. The residue was crystallized from EtOAc and washed with 40% EtOAc/hexanes to give the product, (4.8 g, 75%). NMR(DMSO)d 9.13 (d, 1H, J=8.8 Hz), 5.9 (s, 1H), 3.92-4.02 (m, 1H), 3.20-3.25 (m, 2H), 3.28-3.4 (m, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 2.09 (s, 3H), 1.65-1.90 (m, 2H).

Part F: (S)-2-Chloro-6-methyl-3-nitro-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine: 4-[3-(1,4-dimethoxybutyl)amino]-6-methyl-3-nitropyridone (4.8 g, 16.82 mmol) was dissolved in POCl₃ (50 mL) and stirred at 25° C. for 40 h. Then the reaction was poured into ice/water (500 mL), allowed to react, neutralized with solid NaHCO₃ after EtOAc was added (150 mL) and extracted with EtOAc (2×300 mL). The EtOAc was dried (MgSO₄) and stripped in vacuo to give the product. NMR (CDCl₃)d 7.08 (d, 1H, J=7.7 Hz), 6.65 (s, 1H), 3.85-3.95 (m, 1H), 3.30-3.50 (m, 4H), 3.38 (s, 3H), 3.33 (s, 3H), 2.43 (s, 3H), 1,80-2.02 (m, 2H).

Part G: (S)-3-amino-2-chloro-4-N-(1-methoxymethyl-3-methoxypropyl)-6-methyl-pyridin-4-amine: 2-Chloro-6-methyl-3-nitro-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (-16.82 mmol) was heated at reflux with Fe powder (10 g) in methanol (120 mL) in the presence of glacial acetic acid (10 mL) for 2 h. Then the iron was filtered through celite, the celite was washed with methanol(80 inL) and the filtrate was stripped in vacuo. The residue was dissolved in 10% HCl (120 mL) and EtOAc was added (160 mL). The mixture was neutralized with solid NaHCO₃ and the aqueous layer was extracted with EtOAc (2×100 mL). The combined organic extracts were washed with brine (50 mL), dried (MgSO₄) and stripped in vacuo (4.1 g). NMR(CDCl₃)d 6.4 (s, 1H), 5.2-5.35 (br s, 1H), 3.70-3.80 (m, 1H), 3.2-3.8 (m, 6H), 3.38 (s, 3H), 3.33 (s, 3H), 2.42 (s, 3H), 1.8-2.0 (m, 2H).

Part H: (S)-4-chloro-1-(1-methoxymethyl-3-methoxypropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine: 3-amino-2-chloro-6-methyl-4-N-(1-methoxymethyl-3-methoxypropyl)pyridin-4-amine (4.1 g, 14.98 mmol) was dissolved in a mixture of CH₂ Cl₂ (40 mL) and 50% acetic acid (40 mL) and cooled to 0° C. in an ice bath. To that a solution of NaNO₂ (1.84 g, 26.86 mmol) in water (10 mL) was added dropwise and the reaction was stirred at 0° C. for 30 min and at 25° C. for 1.5 h. Then the acetic acid was neutralized with solid NaHCO₃ and water (80 mL) was added. The mixture was extracted with EtOAc (2×100 mL) and the combined organic extracts were combined and washed with brine (50 mL), dried and stripped in vacuo. The residue was chromatographed on silica gel (40% EtOAc/hexanes eluent) to give the product (4.05 g, 56% overall for the eight steps). NMR(CDCl₃)d 7.25 (s, 1H), 5.04-5.13 (m, 1H), 3.98 (dd, 1H, J₁ =9.9 Hz, J₂ =8.4 Hz), 3.84 (dd, 1H, J₁ =10.2 Hz, J₂ =4.4 Hz), 3.39 (dt, 1H, J₁ =9.9 Hz, J₂ =4.8 Hz), 3.25 (s, 3H), 3.17 (s, 3H), 2.91 (dt, 1H, J₁ =9.5 Hz, J₂ =4.0 Hz), 2.68 (s, 3H), 2.22-2.6 (m, 2H).

Part I: (S)-4-chloro-1-(1-methoxymethyl-3-methoxypropyl)-6-methyl-1H-1,2,3-triazolo[4,5-c]pyridine (2.0 g, 7 mmol) and 2-chloro-4,6-dimethylaniline (1.094 g, 7 mmol) were dissolved in dry THF and cooled to 0° C. in an ice bath. To that a 1 M solution sodium hexamethyldisilazide (16 mL, 16 mmol) was added dropwise and the solution was stirred at 0° C. for 45 min. Then it was quenched with water (30 mL) and partitioned between EtOAc and water (20 mL). The organic extract was washed with brine (50 mL), dried (MgSO₄) and stripped in vacuo. The residue was purified by silica gel chromatography (40% EtOAc/hexanes eluent) and crystallized from hexanes to give the product (2.42 g, 85%), mp 108-109° C., [a]D25 -32.38 (c=0.200 g/dL, CHCl₃) 99.6% ee by chiral HPLC. This was converted to the methylsulfonate salt, mp 98-100° C., after crystallization from ether/hexanes, [a]D25 -29.00 (c=0.200 g/dL, CHCl₃).

EXAMPLE 414A

(R,S)-N- (2-chloro-4,6-dimethylphenyl]-6-methyl-1-(1-methoxymethyl-3-methoxypropyl)-1H-1,2,3-triazolo[4,5-c] pyridin-4-amine

Part A: (R,S)-2-Aminobutyrolactone hydrobromide (8.0 g, 44 inmol) and triphenylmethyl chloride (12.8 g, 46 mmol) were suspended in dry CH₃ CN (80 mL) at 25° C. To that Et₃ N (13.6 mL, 100 mmol) was added dropwise, the reaction mixture was stirred at 25° C. for 4 h and partitioned between EtOAc (120 mL) and water (50 inL). The organic layer was washed with water (50 mL), brine (50 mL), dried (MgSO₄) and stripped in vacuo. The residue was recrystallized from EtOAc/hexanes to give 2-triphenylmethylamino-butyrolactone (10.5 g).

Part B: Lithium aluminum hydride (1.4 g, 36 mmol) was suspended in dry THF (50 mL) and cooled to 0° C. in an ice bath. To that a solution of 2-triphenylmethylamino-butyrolactone (11 g, 31.9 mmol) in dry THF (70 mL) was added dropwise over a period of 20 min. After the addition was over the reaction mixture was stirred at 0° C. for 1 h, at 25° C. for 3h and quenched by the sequential addition of water (2 mL) 1 N NaOH (2 mL) and water (3 mL), and diluted with ether (150 mL). The precipitated solids were filtered off and the filtrate was concentrated in vacuo to give (R,S)-2-N-triphenylamino-1,4-butanediol. This was used in the same synthetic scheme as previously described for the chiral material (Example 414, Parts C-I) to obtain the racemic material.

The compounds listed in Table 8 were prepared by the methods exemplified in Examples 221-232, 259, 414 and 414A.

                  TABLE 8                                                          ______________________________________                                         1H-1,2,3-triazolo[4,5-c]pyridines:                                              ##STR36##                                                                     Ex.                                                                            No.  R.sup.3        Ar             m.p. (° C.)                          ______________________________________                                         415  CH(Et).sub.2   4-Br-2,6-(Me).sub.2 -Ph                                                                       191-192                                     416  CH(Et).sub.2   2,6-(Me).sub.2 -4-SMe-Ph                                                                      172-173                                     417  CH(Et).sub.2   2-Cl-4,6-(Me).sub.2 -Ph                                                                       171-172                                     418  CH(Et).sub.2   2,4-(Cl).sub.2 -6-Me-Ph                                                                       164-165                                     419  CH(Et).sub.2   2,4-(Me).sub.2 -Ph                                                                             90-91                                      420  CH(Et).sub.2   2-Me-4-OMe-Ph  104-105                                     421  CH(Et).sub.2   2-Br-4,6-(Me).sub.2 -Ph                                                                       178-179                                     422  CH(Et).sub.2   4-CN-2,6-(Cl).sub.2 -Ph                                                                       189-190                                     423  CH(Et).sub.2   3-Br-2,4,6-(Me).sub.3 -Ph                                                                     156-157                                     424  CH(Et).sub.2   4-Br-2-SMe-Ph  112-114                                     425  CH(Et).sub.2   2-CN-4,6-Me.sub.2 -Ph                                                                         181-183                                     426  CH(Et).sub.2   2-Br-5-F-4-Me-Ph                                                                              132-134                                     427  CH(Et).sub.2   4-Br-5-F-2-Me-Ph                                                                              115-116                                     428  CH(Et).sub.2   2,4-Br.sub.2 -Ph                                                                              164-166                                     429  CH(Et).sub.2   4-Ac-2-SMe-Ph  142-144                                     430  CH(Et).sub.2   4-Br-2-Cl-Ph   152-153                                     431  CH(Et).sub.2   2,4-Cl.sub.2 -Ph                                                                              134-135                                     432  CH(Et).sub.2   2,4-Me2-6-SMe-Ph                                                                              135-136                                     433  CH(Et)n-Pr     2,4,6-(Me).sub.3 -Ph                                                                          117-118                                     434  CH(Et)CH.sub.2 OMe                                                                            4-Br-2,6-(Me).sub.2 -Ph                                                                       165-166                                     435  CH(Et)CH.sub.2 OMe                                                                            2-Cl-4,6-(Me).sub.2 -Ph                                                                       126-127                                     436  CH(Et)CH.sub.2 OMe                                                                            3-Br-2,4,6-(Me).sub.3 -Ph                                                                     117-118                                     437  CH(Et)CH.sub.2 OMe                                                                            2,4-(Cl).sub.2 -6-Me-Ph                                                                       131-134                                     438  CH(Et)CH.sub.2 OMe                                                                            2-Br-4,6-(Me).sub.2 -Ph                                                                       127-128                                     439  CH(Et)CH.sub.2 OMe                                                                            4-Br-2-Cl-6-Me-Ph                                                                             136-137                                     440  CH(Et)CH.sub.2 OMe                                                                            4-Br-2,6-(Cl).sub.2 -Ph                                                                       119-120                                     441  CH(Et)CH.sub.2 OMe                                                                            2,4-(Me).sub.2 -Ph                                                                             76-77                                      442  CH(Et)CH.sub.2 OMe                                                                            4-MeO-2-Me-Ph   76-77                                      443  CH(Et)CH.sub.2 OMe                                                                            2,4,5-(Me).sub.3 -Ph                                                                           94-95                                      444  CH(Et)CH.sub.2 OMe                                                                            2-Cl-4,6-(OMe).sub.2 -Ph                                                                      167-168                                     445  CH(Et)CH.sub.2 OMe                                                                            2,4,5-(Cl).sub.3 -Ph                                                                          151-152                                     446  CH(Et)CH.sub.2 OMe                                                                            2,5-(Cl).sub.2 -4-NO.sub.2 -Ph                                                                157-158                                     447  CH(Et)CH.sub.2 OMe                                                                            2-CN-4,5-(OMe).sub.2 -Ph                                                                      162-163                                     448  CH(Et)CH.sub.2 OMe                                                                            2-Me-4,5-(OMe).sub.2 -Ph                                                                      118-119                                     449  CH(Et)CH.sub.2 OMe                                                                            2,6-Cl.sub.2 -4-OMe-Ph                                                                        136-137                                     450  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Br-2-OMe-6-Me-Ph                                                                            159-162                                     451  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Br-5-F-2-Me-Ph                                                                              111-113                                     452  CH(Et)CH.sub.2 OCH.sub.3                                                                      2-CN-4,6-Me.sub.2 -Ph                                                                         154-156                                     453  CH(Et)CH.sub.2 OCH.sub.3                                                                      2-OMe-4,6-Me.sub.2 -Ph                                                                        115-116                                     454  CH(Et)CH.sub.2 OCH.sub.3                                                                      2-Ac-4-Cl-6-Me-Ph                                                                             127-129                                     455  CH(Et)CH.sub.2 OCH.sub.3                                                                      2-Br-4,6-F.sub.2 -Ph                                                                          138-140                                     456  CH(Et)CH.sub.2 OCH.sub.3                                                                      2,4,6-Me.sub.3 -Ph                                                                            119-121                                     457  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Br-2-SMe-Ph   70-73                                      458  CH(Et)CH.sub.2 OCH.sub.3                                                                      2,4-Br.sub.2 -Ph                                                                              119-120                                     459  CH(Et)CH.sub.2 OCH.sub.3                                                                      2,4,6-Me.sub.3 -Ph                                                                            113-115                                     460  CH(Et)CH.sub.2 OCH.sub.3                                                                      2,4,6-Me.sub.3 -Ph                                                                            113-115                                     461  CH(Et)CH.sub.2 OCH.sub.3                                                                      2,4-Me.sub.2 -6-SMe-Ph                                                                        104-106                                     462  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Br-2-Me-Ph   amorph.                                     463  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-I-2-Me-Ph    103-105                                     464  CH(Et)CH.sub.2 OCH.sub.3                                                                      3-F-2,4,6-Me.sub.3 -Ph                                                                        amorph.                                     465  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Cl-2-Me-Ph   104-105                                     466  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Br-2,6-F.sub.2 -Ph                                                                          138-140                                     467  CH(Et)CH.sub.2 OCH.sub.3                                                                      4-Cl-2-CN-6-Me-Ph                                                                             177-180                                     468  CH(CH.sub.2 OMe).sub.2                                                                        2,4,6-(Me).sub.3 -Ph                                                                          115-116                                     469  CH(CH.sub.2 OMe).sub.2                                                                        4-Br-2,6-(Me).sub.2 -Ph                                                                       145-146                                     470  CH(CH.sub.2 OMe).sub.2                                                                        2,4-(Cl).sub.2 -6-Me-Ph                                                                       111-112                                     471  CH(CH.sub.2 OMe).sub.2                                                                        3-Br-2,4,6-(Me).sub.3 -Ph                                                                     105-106                                     472  CH(CH.sub.2 OMe).sub.2                                                                        2,4,5-(Me).sub.3 -Ph                                                                          110-111                                     473  CH(CH.sub.2 OMe).sub.2                                                                        2-Br-4-CH(Me).sub.2 -Ph                                                                       107-108                                     474  CH(CH.sub.2 OMe).sub.2                                                                        2-Br-4,6-(Me).sub.2 -Ph                                                                        83-84                                      475  CH(CH.sub.2 OMe).sub.2                                                                        2,4-(Me).sub.2 -Ph                                                                             72-73                                      476  CH(CH.sub.2 OMe).sub.2                                                                        4-MeO-2-Me-Ph   65-67                                      477  CH(CH.sub.2 OMe).sub.2                                                                        4-CH(Me).sub.2 -Ph                                                                            oil                                         478  CH(CH.sub.2 OMe).sub.2                                                                        2,5-Cl.sub.2 -4-N(Me).sub.2 -Ph                                                               110-111                                     479  CH(CH.sub.2 OMe).sub.2                                                                        2-Me-4,5-(OMe).sub.2 -Ph                                                                      111-112                                     480  CH(CH.sub.2 OMe).sub.2                                                                        4-Cl-2,5-(OMe).sub.2 -Ph                                                                      167-168                                     481  CH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,5-(Me).sub.2 -Ph                                                                       169-170                                     482  CH(CH.sub.2 OMe).sub.2                                                                        2,6-(Cl).sub.2 -4-OMe-Ph                                                                      145-146                                     483  CH(CH.sub.2 OMe).sub.2                                                                        4-t-Bu-2,6-(Me).sub.2 -Ph                                                                     134-135                                     484  CH(CH.sub.2 OMe).sub.2                                                                        4-Cl-2-Me-5-NO.sub.2 -Ph                                                                      163-164                                     485  CH(CH.sub.2 OMe).sub.2                                                                        4-Br-2-Cl-5-Me-Ph                                                                             159-160                                     486  CH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4-OMe-6-Me-Ph                                                                            117-118                                     487  CH(CH.sub.2 OMe).sub.2                                                                        4-Cl-2,5-Me.sub.2 -Ph                                                                         115-116                                     488  CH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4-CN-6-Me-Ph                                                                             127-128                                     489  CH(CH.sub.2 OMe).sub.2                                                                        4-Br-2,6-(Et).sub.2 -Ph                                                                       168-169                                     490  CH(CH.sub.2 OMe).sub.2                                                                        4-Br-2-Cl-6-Me-Ph                                                                             104-105                                     491  CH(CH.sub.2 OMe).sub.2                                                                        2-Cl-4,6-(OMe).sub.2 -Ph                                                                      139-140                                     492  CH(CH.sub.2 OMe).sub.2                                                                        2-Br-4,6-(OMe).sub.2 -Ph                                                                      155-156                                     493  CH(CH.sub.2 OMe).sub.2                                                                        5-Cl-4-NMe.sub.2 -2-OMe-Ph                                                                    110-111                                     494  CH(CH.sub.2 OMe).sub.2                                                                        2,4-(Cl).sub.2 -5-CF.sub.3 -Ph                                                                162-163                                     495  CH(CH.sub.2 OMe).sub.2                                                                        4-Cl-2-OMe-5-CF.sub.3 -Ph                                                                     161-162                                     496  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Cl-2-Et-6-Me-Ph                                                                             101-103                                     497  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-F-4,6-Me.sub.2 -Ph                                                                          172-174                                     498  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2,4-Me.sub.2 -6-SMe-Ph                                                                        147-148                                     499  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Br-4,6-Me.sub.2 -Ph                                                                         144-147                                     500  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Cl-2,6-Me.sub.2 -Ph                                                                          97-100                                     501  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Br-2-Et-6-Me-Ph                                                                             111-113                                     502  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2,4,6-Me.sub.3 -Ph                                                                            115-116                                     503  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Br-2,6-Me.sub.2 -Ph                                                                         amorph.                                     504  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Br-2-OMe-6-Me-Ph                                                                            131-133                                     505  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-4,6-Me.sub.2 -Ph                                                                         127-129                                     506  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-I-4,6-Me.sub.2 -Ph                                                                          150-152                                     507  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-4-I-6-Me-Ph                                                                              119-120                                     508  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           3-F-2,4,6-Me.sub.3 -Ph                                                                        amorph.                                     509  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-4,6-Me.sub.2 -Ph                                                                         127-129                                     510  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-4,6-Me.sub.2 -Ph                                                                         108-109                                     511  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Br-6-F-4-Me-Ph                                                                              150-152                                     512  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-5-F-4,6-Me.sub.2 -Ph                                                                     107-108                                     513  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           3-F-2,4,6-Me.sub.3 -Ph                                                                        117-119                                     514  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           3-F-2,4,6-Me.sub.3 -Ph                                                                        117-119                                     515  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2-Cl-5-F-4,6-Me.sub.2 -Ph                                                                     107-109                                     516  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Br-2,6-Me.sub.2 -Ph                                                                         --                                          517  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           4-Br-2,6-Me.sub.2 -Ph                                                                         amorph.                                     518  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2,4,5-Me.sub.3 -Ph                                                                            oil                                         519  CH(CH.sub.2 OMe)C.sub.2 H.sub.4 OMe                                                           2,4,5-Me.sub.3 -Ph                                                                            oil                                         520  CH(CH.sub.2 OMe)C.sub.3 H.sub.6 OMe                                                           2,4,6-Me.sub.3 -Ph                                                                            128-130                                     521  CH(CH.sub.2 OMe)C.sub.3 H.sub.6 OMe                                                           4-Cl-2,6-Me.sub.2 -Ph                                                                         114-115                                     522  CH(Bz)CH.sub.2 OMe                                                                            2,4,6-(Me).sub.3 -Ph                                                                           55-57                                      523  CH(Bz)CH.sub.2 OMe                                                                            2,4-(Cl).sub.2 -6-Me-Ph                                                                        64-65                                      ______________________________________                                          Note: (+), (-), (R) or (S) denotes respective isomers.                   

The compounds listed in table 9 were prepared by the methods exemplified in Examples 209-211 using the intermediate from example 259, part G.

                  TABLE 9                                                          ______________________________________                                         1H-imidazo[4,5-c]pyridines:                                                     ##STR37##                                                                     Ex.                                                                            No.   Ar           R.sup.2                                                                               R.sup.3   m.p. (° C.)                         ______________________________________                                         524   2-Cl-4,6-(Me).sub.2 -Ph                                                                     H      CH(CH.sub.2 OCH.sub.3).sub.2                                                             129-130                                    525   2-Cl-4,6-(Me).sub.2 -Ph                                                                     Me     CH(CH.sub.2 OCH.sub.3).sub.2                                                             156-157                                    ______________________________________                                    

EXAMPLE 526

This example illustrates an alternative method for making the compound of Example 32.

Part A. (±)-1-Methoxy-2-butanol Methanesulfonate (1). A solution of l-methoxy-2-butanol (52.08 g, 57.23 mL, 0.5 mol) and Et₃ N (108.2 mL, 0.75 mol, 1.5 equiv) in CH₂ Cl₂ (500 mL) was treated dropwise with methanesulfonyl chloride (68.73 g, 46.44 mL, 0.6 mol, 1.2 equiv) at 0° C. under N₂. The reaction mixture was warmed to 25° C. and stirred at 25° C. for an additional 4 h before being quenched with H₂ O (300 mL). The two layers were separated, and the aqueuos was extracted with CH₂ Cl₂ (3×100 mL). The combined CH₂ Cl₂ extracts were washed with H₂ O (2×200 mL) and saturated aqueuos NaCl (200 mL), dried (MgSO₄), and concentrated in vacuo. The residue was dried enough in vacuo to afforded the desired mesylate 1 (85-90.0 g, 91 g theoretical, 93-98%) as a pale-yellow oil, which was pure enough and directly used in the next reaction without further purification.

The analytically pure sample of 1 was obtained by silicon-gel column chromatography purification and 1 was obtained as a colorless oil.

Part B. (±)-1-Methoxy-2-butyl Azide (2). A solution of crude mesylate 1 (90.0 g, 0.495 mol) in DMF (500 mL) was treated with NaN₃ (48.22g, 0.74 mol, 1.5 equiv) at 25° C. under N₂. The resulting reaction mixture was warmed to 55-60° C. for 6-8 h with stirring before being quenched with H₂ O (500 mL). The pale-yellow solution was then extracted with EtOAc or Et₂ O (4×200 mL). The combined EtOAc (or Et₂ O) extracts were washed with H₂ O (3×500 mL), dried (MgSO₄), and concentrated in vacuo. The residual solution was found to contain desired azide 2 (60.3 g, 64.5 g theoretical, 94%), which was found to be pure enough and directly used in the following reaction without further purification.

The analytically pure sample of 2 was obtained by SiO₂ column chromatography purification as a colorless, low boiling-point liquid.

Part C. (±)-4-Amino-5-carbamoyl-1-(1-methoxy -2-)butyl-1H-1,2,3-triazole (3). A suspension of cyanoacetamide (46.5 g, 0.553 mol, 1.2 equiv) in absolute EtOH (200 mL) was treated with EtONa (62.73 g, 0.922 mol, 2.0 equiv) at 25° C. under N₂, and the resulting mixture was warmed to reflux for 15 min under N₂. The cooled mixture was then treated with a solution of 1-methoxy-2-butyl azide 2 (59.5 g, 0.467 mol) in Et₂ O and the mixture was diluted with additional EtOH (260 mL) at 25° C. The resulting reaction mixture was warmed to reflux and stirred for 6-8 h at reflux before being cooled to room tempearture. The solvent was removed in vacuo, and the residue was treated with H₂ O (300 mL) and EtOAc (300 mL). The two layers were separated, and the aqueous was extracted with EtOAc (5×100 mL). The combined EtOAc extracts were washed with saturated aqueous NaCl (50 mL), dried in vacuo, and concentrated in vacuo. The residual yellow solid was directly recrystalized from MeOH (100-150 mL) to afford the desired 1,2,3-triazole 3 (70.7 g, 98.2 g theoretical, 72%) as white crystals.

Part D. (±)-9-(1-Methoxy-2-)butyl-2-methyl-8-azaadenine (4). Method A: A solution of 3 (10.65 g, 0.05 mol) in absolute EtOH (50 inL) was treated with EtONa (6.8 g, 0.1 mol, 2.1 equiv) and EtOAc (8.8 g, 10.0 mL, 0.5 mol, 10 equiv) at 25° C. under N₂, and the resulting reaction mixture was warmed to reflux with stirring for 6-8 h before being quenched with H₂ O (50 mL). The solution was then concentrated in vacuo to remove most of EtOH. The residue was treated with H₂ O (50 mL), acidified with concentrated HCl (pH 6-7), and extracted with EtOAc (5×50 mL). The combined EtOAc extracts were washed with saturated aqueous NaCl (20 mL), dried (MgSO₄), and concentrated in vacuo. The residual pale-yellow solid was directly recrystalized from 80% EtOAc-Hexane or EtOH to afford 8-azaadenine 4 (8.4 g, 11.85 theoretical, 71%) as white crystals.

Method B: A suspension of cyanoacetamide (47.1 g, 0.561 mol, 1.2 equiv) in absolute EtOH (200 mL) was treated with EtONa (95.3 g, 1.4 mol, 3.0 equiv) at 25° C. under N₂, and the resulting mixture was warmed to reflux for 15 min. under N₂. The cooled mixture was then treated with a solution of 1-methoxy-2-butyl azide 2 (60.3 g, 0.467 mol) in EtOAc (or Et₂ O) in absolute EtOH (170 mL) at 25° C., and the resulting reaction mixture was warmed to reflux and stirred 4-6 h at reflux before being cooled to RT. EtOAc (120 mL) was added to the reaction mixture, and the resulting mixture was warmed to reflux for an additional 6-10 h. The cooled reaction mixture was treated with H₂ O (200 mL), and the solution was concentrated in vacuo to remove most of EtOH. The residue was treated with H₂ O (100 mL) and acidified with concentrated HCl (pH 6-7), and extracted with EtOAc (6×150 mL). The combined EtOAc extracts were washed with saturated aqueous NaCl (100 mL), dried (MgSO₄), and concentrated in vacuo. The residual pale-yellow solid was recrystalized from 80% EtOAc-Hexane (or EtOH) to afford 8-azaadenine 4 (70.8 g, 110.7 g theoretical, 64% for two steps) as white crystals.

Part E. (±)-4-Chloro-1-(1-methoxy-2-)butyl-2-methyl-8-azaadenine (5). Method A: A solution of 4 (6.78 g, 0.017 mol) in POCl₃ (30 mL) was warmed to reflux for 3 h. The excess POC₁₃ was removed in vacuo, and the residue was treated with H₂ O (50 mL) and EtOAc (50 mL). The two layers were separated, and the aqueous was extracted with EtOAc (3×50 inL). The combined EtOAc extracts were washed with H₂ O (2×50 mL) and saturated aqueous NaCl (30 mL), dried (MgSO₄), and concentrated in vacuo. Flash chromatography (SiO₂, 10-20% EtOAc-Hexane gradient elution) afforded 5 (6.65 g, 7.30 g theoretical, 91%) as a colorless oil, which solidified upon standing in vacuo.

Method B: A solution of 4 (170 mg, 0.72 mmol) was treated with POCl₃ (2 mL) and N,N-diethylaniline (0.5 mL) at 25° C. under N₂, and the resulting mixture was warmed to reflux for 4-6 h. The excess POCl₃ was removed in vacuo, and the residue was directly purified by flash chromatography (SiO₂, 10-20% EtOAc-Hexane gradient elution) to afford 5 (159 mg, 184 mg theoretical, 86%) as a colorless oil, which solidified in vacuo. The product obtained by Method B was identical in all comparable respects with that obtained from Method A.

Part F. (±)-1-(1-Methoxy-2-)butyl-2-methyl-4-[(2,4,6-trimethyl)phenyl]amino-8-azaadenine (6).

A solution of 5 (7.0 g, 0.0274 mol) in toluene (50 mL) was treated with 2,4,6-trimethylphenyl amine (8.1 g, mL, 0.06 mol, 2.2 equiv) at 25° C. under N₂. The resulting reaction mixture was warmed to reflux for 6-8 h under N₂. The white solid (2,4,6-trimethylaniline HCl salt) was filtered and the solid was washed with toluene (10-20 mL). The filtrate was concentrated in vacuo. The residual pale-yellow solid was recrystalized from 30% EtOAc-Hexane to afford the title compound 6 (7.9 g, 9.7 g theoretical, 81%) as white crystals.

EXAMPLE 527

This illustrates an alternative method for making the compound of Example 259.

Part A. 2-(2-Chloro-4,6-dimethyl)-phenylamino-4-(1,3-dimethoxy-2-propyl)amino-6-methyl-3-nitropyridine (3). A suspention of p-toluenesulfonic acid monohydrate (6.84 g., 36 mmol., 1.2 equiv.) in toluene (150 mL) was warmed to reflux for 2 h, and the azeotropic mixture of water and toluene (50 mL) was removed during the course of the azeotropic distillation. After the mixture was cooled down to room temperature, 2-chloro-4-(1,3-dimethoxy-2-propyl)amino-6-methyl-3-nitropyridine hydrochloride salt (1, 9.8 g, 30 mmol) and 2-chloro-4,6-dimethylaniline (2, 4.68 g, 30 mmol, 1.0 equiv) were introduced to the reaction mixture, and the resulting reaction mixture was warmed to reflux for 6 h. The reaction mixture was then cooled down to room temperature, and was subsequently treated with saturated aqueous NaHCO₃ solution (100 mL) and tert-butyl methyl ether (TBME, 100 mL). The two layers were separated, and the aqueous layer was extracted with TBME (2×50 mL). The combined organic extracts were washed with saturated aqueous NaHCO₃ solution (50 mL), H₂ O (50 mL), and saturated aqueous NaCl solution (50 mL), dried (MgSO₄), and concentrated in vacuo. The residue was then directly purified by flash column chromatography (SiO₂, 15-30% EtOAc-hexane gradient elution) to afford the desired 3 (7.63 g, 12.26 g theoretical, 62.3%) as a yellow oil, which was solidified upon standing at room tempreture in vacuo. The analytically pure material was obtained from recrystalization of the chromatographically pure 3 from TBME/hexane (1:5) as yellow crystals.

Part B. 3-Amino-2-(2-chloro-4,6-dimethyl)-phenylamino-4-(1,3-dimethoxy-2-propyl)amino-6-methylpyridine (4). A solution of 3 (3.0 g, 7.34 mmol) in THF (10 mL) was treated with ammonium hydroxide (28-30% aqueous solution, 10 mL, 73 mmol, 10 equiv), Na₂ S₂ O₄ (6.38 g, 36.7 mmol, 5.0 equiv) and H₂ O (10 mL) at room temperature under N₂. The resulting reaction mixture was then stirred at room temperature for 12 h before being treated with H₂ O (20 mL) and EtOAc (50 mL). The two layers were separated, and the aqueous layer was extracted with EtOAc (4×20 mL). The combined organic extracts were washed with saturated NaHCO₃ aqueous solution (20 mL), H₂ O (20 mL), and saturated NaCl aqueous solution (20 mL), dried (MgSO₄), and concentrated in vacuo. The residual oil was solidified upon standing at room temperature in vacuo to afford the desired 4 (2.5 g, 2.78 g theoretical, 90%) as yellow solids, which was found to be pure enough to go directly to the next reaction without further purification. The analytically pure product was obtained as yellow crystals by recrystalization of the crude material from TBME.

Part C. 3-(2-Chloro-4,6-dimethyl)phenyl-7-(1,3-dimethoxy-2-propyl)amino-5-methyl-[1,2,3]triazolo[4,5-b]pyridine (5) and 4-(2-Chloro-4,6-dimethyl)phenylamino-1-(1,3-dimethoxy-2-)propyl-6-methyl-[1,2,3]triazolo[4,5-c]pyridine (6).

Method A: A solution of 4 (1.5 g, 4.0 mmol) in CH₂ Cl₂ (10 mL) and HOAc (1.14 mL, 20 mmol, 5.0 equiv) at 0° C. under N₂ was treated dropwise with a solution of NaNO₂ (331 mg, 4.8 mmol, 1.2 equiv) in H₂ O (3.0 mL). The reaction mixture was kept at 0-5° C. during the addition of the aqueous NaNO₂ solution. The resulting reaction mixture was then warmed gradually to room temperature for an additional 30 min before being treated with H₂ O (20 mL) and CH₂ Cl₂ (30 mL). The two layers were separated, and the aqueous layer was extracted with CH₂ Cl₂ (2×20 mL). The combined organic extracts were washed with H₂ O (20 mL), saturated aqueous NaHCO₃ solution (2×10 mL), H₂ O (20 mL), and saturated aqueous NaCl solution (20 mL), dried (MgSO₄), and concentrated in vacuo. The oily residue was found to be a mixture of 5 and 6 (3:1, 1.4 g, 1.56 g theoretical, 90%) by ¹ H NMR, which was then separated by flash column chromatography purification (SiO₂, 15-30% EtOAc-hexane gradient elution) to afford 5 (967 mg, 62%) and 6 (320 mg, 21%). The analytically pure 5 was obtained by recrystalization of the chromatographically pure material from TBME-heptane (1:4).

Method B: A solution of 4 (1.5 g, 4.0 mmol) in THF (10 mL) was treated with HBF₄ (54% solution in ether, 1.3 g, 1.1 mL, 8.0 mmol, 2.0 equiv) at 0° C. under N₂, and the resulting mixture was then treated dropwise with isoamyl nitrite (643 mg, 0.74 mL, 6.0 mmol, 1.5 equiv). The reaction mixture was kept at 0-5° C. during the addition of isoamyl nitrite. The resulting reaction mixture was then warmed gradually to room temperature for an additional 30 min before being treated with H₂ O (20 mL) and TBME (30 mL). The two layers were separated, and the aqueous layer was extracted with TBME (20 mL). The combined organic extracts were washed with H₂ O (20 mL), saturated aqueous NaHCO₃ solution (20 mL), H₂ O (20 mL), and saturated aqueous NaCl solution (20 mL), dried (MgSO₄), and concentrated in vacuo. The residual oil was found gradually solidified upon standing in vacuo at room temperature, which was found to be almost exclusively 5 (5:6>95:5) by ¹ H NMR. The crude solids were recrystalized from TBME-heptane (1:5) to afford pure 5 (1.45 g, 1.56 g theoretical, 93%) as off-white crystals.

Part D. 4-(2-Chloro-4,6-dimethyl)-phenylamino-1-(1,3-dimethoxy-2-)propyl-6-methyl-[1,2,3]triazolo[4,5-c]pyridine (6).

Method A: A solution of 5 (195 mg, 0.5 mmol) in anhydrous DMF (2 mL) was cooled down to 0° C. and treated with NaH (60% disposition in mineral oil, 24 mg, 0.6 mmol, 1.2 equiv) under N₂. The resulting reaction mixture was gradually warmed to room temperature for 2 h before being warmed to 70° C. for 2 h. The reaction mixture was then cooled down to room temperature and treated with TBME (20 mL) and H₂ O (20 mL). The two layers were separated, and the aqueous layer was extracted with TBME (2×10 mL) The combined organic extracts were washed with H₂ O (20 mL), and saturated aqueous NaCl (20 mL), dried (MgSO₄), and concentrated in vacuo. The residual oil was solidified upon standing at room temperature in vacuo to afford pure 6 (178 mg, 195 mg theoretical, 92 %).

Method B: A solution of mixed 5 and 6 (5:6=3:1, 780 mg, 2.0 mmol) in anhydrous 1-methyl-2-pyrrolidone (NMP, 8 mL) was cooled down to 0° C. and treated with NaH (60% disposition in mineral oil, 96 mg, 2.4 mmol, 1.2 equiv) at 0° C. under N₂. The resulting reaction mixture was stirred at 0° C. for 10 min before being warmed to room temperature for overnight. The isomerization was found to be very slow at room temperature, so the reaction mixture was further to warmed to 70° C. for 6 h before the isomerization was completed. The reaction mixture was then cooled down to room temperature and treated with TBME (20 mL) and H₂ O (20 mL). The two layers were separated, and the aqueous layer was extracted with TBME (2×20 mL). The combined organic extracts were washed with H₂ O (2×20 mL), and saturated aqueous NaCl (20 mL), dried (MgSO₄), and concentrated in vacuo. The residual oil was solidified upon standing at room temperature in vacuo to afford pure 6 (726 mg, 780 mg theoretical, 93%). Compound 6 can be converted to the corresponding mesylate salt by the method of Example 259, Part J.

The method of Example 527 can be used to produce other compounds of Formula I wherein X is CR¹, Y is N, and Z is NR³, such as the compounds of Examples 221-232, 414 and 414a and the compounds of Table 8.

Utility

CRF-R1 Receptor Binding Assay for the Evaluation of Biological Activity

The following is a description of the isolation of cell membranes containing cloned human CRF-RI receptors for use in the standard binding assay as well as a description of the assay itself.

Messenger RNA was isolated from human hippocampus. The mRNA was reverse transcribed using oligo (dt) 12-18 and the coding region was amplified by PCR from start to stop codons The resulting PCR fragment was cloned into the EcoRV site of pGEMV, from whence the insert was reclaimed using XhoI+XbaI and cloned into the XhoI+XbaI sites of vector pm3ar (which contains a CMV promoter, the SV40 `t` splice and early poly A signals, an Epstein-Barr viral origin of replication, and a hygromycin selectable marker). The resulting expression vector, called phchCRFR was transfected in 293EBNA cells and cells retaining the episome were selected in the presence of 400 mM hygromycin. Cells surviving 4 weeks of selection in hygromycin were pooled, adapted to growth in suspension and used to generate membranes for the binding assay described below. Individual aliquots containing approximately 1×10⁸ of the suspended cells were then centrifuged to form a pellet and frozen.

For the binding assay a frozen pellet described above containing 293EBNA cells transfected with hCRFR1 receptors is homogenized in 10 ml of ice cold tissue buffer (50 mM HEPES buffer pH 7.0, containing 10 mM MgCl₂, 2 mM EGTA, 1 mg/l aprotinin, 1 mg/ml leupeptin and 1 mg/ml pepstatin). The homogenate is centrifuged at 40,000× g for 12 min and the resulting pellet rehomogenized in 10 ml of tissue buffer. After another centrifugation at 40,000× g for 12 min, the pellet is resuspended to a protein concentration of 360 mg/ml to be used in the assay.

Binding assays are performed in 96 well plates; each well having a 300 ml capacity. To each well is added 50 ml of test drug dilutions (final concentration of drugs range from 10⁻¹⁰ -10⁻⁵ M), 100 ml of ¹²⁵ I-ovine-CRF (¹²⁵ I-o-CRF) (final concentration 150 pM) and 150 ml of the cell homogenate described above. Plates are then allowed to incubate at room temperature for 2 hours before filtering the incubate over GF/F filters (presoaked with 0.3% polyethyleneimine) using an appropriate cell harvester. Filters are rinsed 2 times with ice cold assay buffer before removing individual filters and assessing them for radioactivity on a gamma counter.

Curves of the inhibition of ¹²⁵ I-o-CRF binding to cell membranes at various dilutions of test drug are analyzed by the iterative curve fitting program LIGAND [P. J. Munson and D. Rodbard, Anal. Biochem. 107:220 (1980), which provides Ki values for inhibition which are then used to assess biological activity.

A compound is considered to be active if it has a K_(i) value of less than about 10000 nM for the inhibition of CRF.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

Inhibition of CRF-stimulated adenylate cyclase activity was performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays were carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5'-triphosphate, 100 mM oCRF, antagonist peptides (concentration range 10⁻⁻ to 10^(-6m)) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions were initiated by the addition of 1 mM ATP/³² P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³ H]cAMP (approximately 40,000 dpm) was added to each tube prior to separation. The separation of [³² p]cAMP from [³² P]ATP was performed by sequential elution over Dowex and alumina columns. Recovery was consistently greater than 80%.

Some compounds of this invention were tested in this assay and found to be active.

In vivo Biological Assay

The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990)

Compounds may be tested in any species of rodent or small mammal. Disclosure of the assays herein is not intended to limit the enablement of the invention.

Compounds of this invention have utility in the treatment of abnormalities in humans and other mammals which are associated with corticotropin releasing factor and/or a receptor for corticotropin releasing factor. This includes depression, affective disorders, anxiety, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, epilepsy, seizures, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorders, fertility problems. It includes numerous other disorders such as those mentioned in the disclosure of Pfizer WO95/33750, at pages 7 and 8, which is incorporated herein by reference.

Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent's site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.

Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease. 

What is claimed is:
 1. A CRF antagonist compound of formula I: ##STR38## or a pharmaceutically acceptable salt or pro-drug form thereof, wherein: X is N;Y is N or CR² ; Z is NR³, O, or S(O)n; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyl, each optionally substituted with 1 to 5 R⁵ groups; R¹ is independently at each occurrence H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, halo, CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, NR⁹ COR¹⁰, --OR¹¹, SH or --S(O)_(n) R¹² ; R² is H, C₁ -C₄ alkyl, C₁ -C₆ cycloalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, C₁ -C₄ haloalkyl, --OR⁷, SH or --S(O)_(n) R¹² ; R³ is H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl or C₄ -C₁₂ cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --CONR⁶ R⁷, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C_(1-C) ₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; R⁴ is H, C₁ -C₄ alkyl, allyl, or propargyl, where C₁ -C₄ alkyl, allyl, or propargyl is optionally substituted with C₃ -C₆ cycloalkyl and where C₁ -C₄ alkyl is optionally substituted with, --OR⁷, --S(O)_(n) R¹² or --CO₂ R⁷ ; R⁵ is independently at each occurrence C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, --CO(NOR⁹)R⁷, CO₂ R⁷, or --S(O)_(n) R⁷, where C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, CO₂ R⁷, --CO(NOR⁹)R⁷, or --S(O)_(n) R⁷ ; R⁶ and R⁷ are independently at each occurrence H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; or NR⁶ R⁷ is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine orthiomorpholine; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; n is independently at each occurrence 0, 1 or 2; provided that R⁴ in formula I is not H: (a) when Y is N, Z is NR³, R¹ is H, R³ is H or benzyl, and Ar is p-methylphenyl; (b) when Y is N, Z is NR³, R¹ is butyl, R³ is benzyl, and Ar is phenyl; (c) when is CH, Z is NR³, R³ is methyl, R¹ is H, and Ar is phenyl or 2-fluorophenyl; (d) when Y is CH, Z is NR³, R³ is methyl, R¹ is Cl and Ar is phenyl; (e) when Y is CH, Z is NR³, R¹ is Cl, R³ is benzyl, and Ar is phenyl or substituted phenyl; (f) when Y is CH, Z is NR³, R³ is p-methylbenzyl, and Ar is phenyl; (g) when Y is CR², Z is NR³, R² is CH₃, R³ is H, and Ar is phenyl or phenyl substituted with methyl, ethyl, isopropyl, fluoro or chloro; (h) when Y is N, Z is NR³, R³ is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or (i) when Y is N, Z is S, R¹ is H, and Ar is 2-bromo-4-isopropylphenyl.
 2. A CRF antagonist compound of claim 1 or a pharmaceutically acceptable salt or pro-drug form thereof, wherein:X is N; Y is N or CR² ; Z is NR³, O, or S(O)_(n) ; Ar is phenyl, pyridyl, each optionally substituted with 1 to 3 R⁵ groups; R¹ is independently at each occurrence H, C₁ -C₄ alkyl, halo, CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, --OR¹¹ or --S(O)_(n) R¹² ; R² is H, C₁ -C₄ alkyl, C₁ -C₆ cycloalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, C₁ -C₄ haloalkyl, --OR⁷ or --S(O)_(n) R¹² ; R³ is H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl or C₄ -C₁₂ cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, --S(O)_(n) R¹³, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, aryl and heteroaryl, where the aryl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R⁷, --CO₂ R⁷, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R⁷, and --NR⁶ R⁷ ; R⁴ is H, C₁ -C₄ alkyl, allyl, or propargyl; R⁵ is independently at each occurrence C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₈ cycloalkylalkyl, --NO₂, halo, --CN C₁ -C₄ haloalkyl, --NR⁶ R⁷, COR⁷ --OR⁷, --CONR⁶ R⁷, --CO(NOR⁹)R⁷, CO₂ R⁷, or --S(O)_(n) R⁷, where C₁ -C₆ alkyl, C₂ -C₆ alkenyl, C₂ -C₆ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, COR⁷, --OR⁷, --CONR⁶ R⁷, CO₂ R⁷, --CO(NOR⁹)R⁷, or --S(O)_(n) R⁷ ; R⁶ and R⁷ are independently at each occurrence H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; or NR⁶ R⁷ is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl; aryl is phenyl or naphthyl optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁸, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, NR⁸ CO₂ R¹², and --NR⁶ R⁷ ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, halo, cyano, --OR⁷, --S(O)_(n) R¹², --CO₂ R⁸, --NR⁸ COR⁷, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹², and --NR⁶ R⁷ ; n is independently at each occurrence 0, 1 or
 2. 3. A CRF antagonist compound of claim 1 selected from the group consisting of:N-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-3-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-5-methyl-3-propyl-3H -1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-{2-bromo-4-(1-methylethyl)phenyl]-3-butyl-N-ethyl-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-3-(cyclopropylmethyl)-N-ethyl-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methyl)ethylphenyl]-5-methyl-3-[(l -methoxymethyl)-2-methoxyethyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-3-(2-methoxyethyl)-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-(2-methoxyethyl)-5-methyl-3H-1,2,3-triazoloi[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-(3-methoxypropyl)-5-methyl-3 H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[1-(1 -methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (S)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[l -(1-methoxymethyl)-2-phenylethyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (S)-methyl 7-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-2-(methylthio)ethyl]3H-1,2,3-triazolo[4,5-d]pyrimidine-3-acetate (±)-N-[2-bromo-4-(1-methylethyl)phenyl]3-1 -ethylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[l -ethylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1 -propylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1 -butylpentyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-[2-bromo-4-(1-methylethyl)phenyl]-3-[l -ethylbutyl]-5-methyl-3H-1,2,3-triazolo[4,5d]pyrimidin-7-amine (±)-7-[2-bromo-4-(1-methylethyl)phenyl]-5-methyl-a-propyl-3H-1,2,3-triazolo[4,5-d]pyrimidine-3-ethanol N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-ethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-3-[1-ethyl propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-(2-bromo-4,6-dimethylphenyl)-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine 5-methyl-N-[4-(1-methylethyl-2-(methylthio)phenyl]-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(trifluoromethyl)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4,6-(dimethoxy)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2,6-dimethyl-4-(methylthio)phenyl)]-5-methyl-3-[1-propylbutyl]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-(4-acetyl-2-bromophenyl)-3-[1-ethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-(4acetyl-2-bromophenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-(4-bromo-2,6-dimethylphenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-[2,6-dimethyl-4-(methylthio)phenyl]-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-(2-bromo-4,6-dimethoxyphenyl)-3-[1-(1-methoxymethyl)propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-(2-chloro-4,6-dimethoxyphenyl)-3-[1-(1-methoxymethylpropyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-methoxymethyl) propyl]-5-methyl-N-(2,4,6-trmethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-ethyl-3-[1-(1-methoxy-methyl)propyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine 3-[1-(1-ethyl)propyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1,(1-ethyl)butyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-ethyl)pentyl]-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidine-7-amine 5-methyl-3-[1-(1-propylbutyl]-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine 3-(2-methoxyethyl)-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-ethyl-3-(2-methoxyethyl)-5-methyl-N-(2,4,6-trimethylphenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-(2-Methyl-4-bromophenyl)-3-[1-(1-propyl)butyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-ethyl)butyl]-5-methyl-N-(2-methyll-4-bromophenyl)-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-(4-bromo-2-methylphenyl)-3-[1-(1-methoxymethyl) propyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-ethyl)pentyl]-5-methyl-N-[2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-ethyl-3-[1-(1-ethyl) pentyl]-5-methyl-N-[2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-ethyl)butyl]-5-methyl-N-[(2,4,6-trimethyl)3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-ethyl-3-[1-(1-ethyl)butyl]-5-methyl-N-[2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine 3-[1-(1-propyl)butyl]-5-methyl-N-[(2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-ethyl-3-[1-(1-propyl) butyl]-5-methyl-N-[2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-3-[1-(1-methoxymethyl) propyl]-5-methyl-N-[2,4,6-trimethyl)-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine (±)-N-ethyl-3-[1-(1-methoxy methyl) propyl}5-methyl-N-[(2,4,6-trimethyl-3-pyridyl-]-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-2,4-dibromophenyl)-5-methyl-3-(1-propyl)butyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[4-acetyl-2-bromphenyl]-5-methyl-3-(1-propyl)butyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-3-[1-(N,N-dimethylamino-methyl)butyl]-5-methyl-3H-1,2,3-triazolo[4,5-d]pyrimidin-7-amine N-[2-bromo-4-(1-methylethyl)phenyl]-2-methyl-9-(l-propylbutyl)-9H-purin-6-amine (±)-N-[2-bromo-4-(1-methylethyl)phenyl]-9-(l-ethylpentyl)-2-methyl-9H-purin-6-amine (±)-N-[2-bromo-4-(trifluoromethyl)phenyl]-9-1-(methoxymethyl)propyl]-2-methyl-9H-purin-6-amine N-[2-bromo-4-(1-methylethyl)phenyl]-N-ethyl-5-methyl-[i ,2,3]thiadiazolo[5,4-d]pyrimidin-7-amine.
 4. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 1. 5. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 2. 6. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim
 3. 7. A method of treating affective disorder, anxiety or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of formula I: ##STR39## or a pharmaceutically acceptable salt, wherein: X is N;Y is N or CR² ; Z is NR³, O, or S(O)n; Ar is phenyl, naphthyl, pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl or pyrazolyi, each optionally substituted with 1 to 5 R⁵ groups; R¹ is independently at each occurrence H, C₁ -C₄ alkyl, C₂ -C₄ alkenyl, C₂ -C₄ alkynyl, halo, CN, C₁ -C₄ haloalkyl, --NR⁹ R¹⁰, NR⁹ COR¹⁰, --OR¹¹, SH or --S(O)_(n) R¹² ; R² is H, C₁ -C₄ alkyl, C₁ -C₆ cycloalkyl, halo, CN, --NR⁶ R⁷, NR⁹ COR¹⁰, C₁ -C₄ haloalkyl, --OR⁷, SH or --S(O)_(n) R¹² ; R³ is H, C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₈ cycloalkyl or C₄ -C₁₂ cycloalkylalkyl each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, --CONR⁶ R⁷, aryl, heteroaryl and heterocyclyl, where the aryl, heteroaryl or heterocyclyl is optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; R⁴ is H, C₁ -C₄ alkyl, allyl, or propargyl, where C₁ -C₄ alkyl, allyl, or propargyl is optionally substituted with C₃ -C₆ cycloalkyl and where C₁ -C₄ alkyl is optionally substituted with, --OR⁷, --S(O)_(n) R¹² or --CO₂ R⁷ ; R⁵ is independently at each occurrence C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, --NO₂, halo, --CN, C₁ -C₄ haloalkyl, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, --CO(NOR⁹)R⁷, CO₂ R⁷, or --S(O)_(n) R⁷, where C₁ -C₁₀ alkyl, C₂ -C₁₀ alkenyl, C₂ -C₁₀ alkynyl, C₃ -C₆ cycloalkyl and C₄ -C₁₂ cycloalkylalkyl are optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₄ alkyl, --NO₂, halo, --CN, --NR⁶ R⁷, --NR⁶ R⁷, NR⁸ COR⁷, NR⁸ CO₂ R⁷, --COR⁷ --OR⁷, --CONR⁶ R⁷, CO₂ R⁷, --CO(NOR⁹)R⁷, or --S(O)_(n) R⁷ ; R⁶ and R₇ are independently at each occurrence H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, C₂ -C₈ alkoxyalkyl, C₃ -C₆ cycloalkyl, C₄ -C₁₂ cycloalkylalkyl, aryl, aryl(C₁ -C₄ alkyl)-, heteroaryl or heteroaryl(C₁ -C₄ alkyl)-; or NR⁶ R⁷ is piperidine, pyrrolidine, piperazine, N-methylpiperazine, morpholine or thiomorpholine; R⁸ is independently at each occurrence H or C₁ -C₄ alkyl; R⁹ and R¹⁰ are independently at each occurrence selected from H, C₁ -C₄ alkyl, or C₃ -C₆ cycloalkyl; R¹¹ is H, C₁ -C₄ alkyl, C₁ -C₄ haloalkyl, or C₃ -C₆ cycloalkyl; R¹² is C₁ -C₄ alkyl or C₁ -C₄ haloalkyl; aryl is phenyl or naphthyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)nR¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heteroaryl is pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzthiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, or indazolyl, each optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; heterocyclyl is saturated or partially saturated heteroaryl, optionally substituted with 1 to 3 substituents independently selected at each occurrence from C₁ -C₆ alkyl, C₃ -C₆ cycloalkyl, halo, C₁ -C₄ haloalkyl, cyano, --OR⁷, SH, --S(O)_(n) R¹³, --COR⁷, --CO₂ R⁷, --OC(O)R¹³, --NR⁸ COR⁷, --N(COR⁷)₂, --NR⁸ CONR⁶ R⁷, --NR⁸ CO₂ R¹³, --NR⁶ R⁷, and --CONR⁶ R⁷ ; n is independently at each occurrence 0, I or 2; provided that R⁴ in formula I is not H: (a) when Y is N, Z is NR³, R3 is cyclopropylmethyl, R1 is H, and Ar is 2-bromo-4-isopropylphenyl, or (b) when Y is N, Z is S, R¹ is H, and Ar is 2-bromo-4-isopropylphenyl.
 8. A method of treating an affective disorder, anxiety, or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim
 2. 9. A method of treating an affective disorder, anxiety, or depression in a mammal comprising administering to the mammal a therapeutically effective amount of a CRF antagonist compound of claim
 3. 